7-phenylpyrazolopyridine compounds

ABSTRACT

A compound represented by the formula:  
                 
 
[wherein R 1  is methoxy, methylthio, ethyl, etc.; R 5  and R 6  are each independently cyclopropylmethyl, (4-tetrahydropyranyl)methyl, etc.; and two of R 40 , R 41  and R 42  are C 1-6  alkoxy while the remaining one is methoxymethyl, etc.], a salt thereof, or a hydrate of the foregoing. This compound has excellent antagonism against corticotropin-releasing factor receptor.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a 37 C.F.R. § 1.53(b) divisional of U.S.application Ser. No. 10/524,662 filed Dec. 13, 2005, which claimspriority on PCT International Application No. PCT/JP2003/013490 filedOct. 22, 2003, which in turn claims priority on U.S. Provisional PatentApplication No. 60/421,071 filed Oct. 25, 2002, and Japanese PatentApplication No. P2002-306695 filed Oct. 22, 2002. Each of theseapplications is hereby incorporated by reference.

TECHNICAL FIELD

The present invention relates to novel compounds havingCorticotropin-Releasing Factor receptor antagonistic activity, saltsthereof and hydrates of the foregoing, to processes for producing thesame and to uses of the same as medicine.

BACKGROUND ART

Corticotropin-Releasing Factor (hereinafter abbreviated as “CRF”) is aneuropeptide consisting of 41 amino acids which was first isolated fromovine hypothalamus [Science, 213, 1394 (1981)], after which its presencewas also confirmed in rat [Proc. Natl. Acad. Sci. USA, 80, 4851 (1983)]and in human [EMBO J. 5, 775 (1983)]. CRF is most abundant in thepituitary gland and hypothalamus, and is also widely distributedthroughout cerebral cortex, cerebellum and other areas of the brain. Itspresence has also been confirmed in peripheral tissue such as theplacenta, adrenal gland, lung, liver, pancreas and gastrointestinaltract [Exp. Clin. Endocrinol. Diabetes, 105, 65 (1997)]. Two subtype CRFreceptor has been described, CRF1 and CRF2, and CRF1 receptor isreported to be widely distributed in cerebral cortex, cerebellum,olfactory bulb, pituitary gland, amygdaloidal nucleus and elsewhere.Recently, 2 subtypes of the CRF2 receptor have been confirmed, CRF2α andCRF2β, of which it has been discovered that CRF2α receptors areabundantly distributed in the hypothalamus, septal nucleus and choroidplexus, while CRF2β receptors are primarily distributed in peripheraltissue such as the skeletal muscle, or in the cerebral blood vessels ofthe central nervous system [Exp. Clin. Endocrinol. Diabetes, 105, 65(1997)]. The fact that each of these receptors has a differentdistribution profile suggests that their roles are also different. CRFis produced and secreted in the hypothalamus and promotes stress-inducedrelease of adrenocorticotropic hormone (ACTH) [Recent Prog. Horm. Res.,39, 245 (1983)]. In addition to its endocrine role, CRF also functionsas a neurotransmitter or neuromodulator in the brain, integratingelectrophysiological, autonomic and behavioral changes in response tostress [Brain Res. Rev., 15, 71 (1990); Pharmacol. Rev., 43, 425(1991)].

CRF has been implicated in a variety of disease to date, as indicated bythe following publications.

It was reported that elevated concentrations of CRF in the cerebrospinalfluid of patients with major depression compared with healthyindividuals; CRF-mRNA levels in the hypothalamus of depressive patientsare higher than that of healthy individuals; CRF receptors in cerebralcortex are reduced in suicide victims; plasma ACTH increase isdiminished with administration of CRF to depressive patients [Journal ofEndocrinology, 160, 1 (1999)]; CRF levels in the cerebrospinal fluid ofsome anxiety patients with obsessive-compulsive disorder, posttraumaticstress disorder or Tourette's syndrome are higher than in that ofhealthy individuals [Journal of Endocrinology, 160, 1 (1999)]; plasmaACTH increase is diminished with administration of CRF to panic disorderpatients [Exp. Clin. Endcrinol. Diabetes, 105, 65 (1997)]; anxietybehavior has been observed in experimental animals by intracerebraladministration of CRF. In addition, anxiety behavior is observed morefrequently in CRF overexpressing mice than in normal mice [Journal ofEndocrinology, 160, 1 (1999)], and CRF levels in the locus coeruleus arereduced by administration of anxiolytics [Exp. Clin. Endcrinol.Diabetes, 105, 65 (1997)]. Also, α-helical CRF(9-41), a peptide CRFantagonist, exhibits an antianxiety action in animal models [Brain Res.,509, 80 (1990); Regulatory Peptides, 18, 37 (1987); J. Neurosci., 14(5),2579 (1994)]; and abnormal behavior withdrawal from alcohol or addictivedrugs such as cocaine are inhibited by α-helical CRF(9-41), a peptideCRF antagonist [Psychopharmacology, 103, 227 (1991)].

CRF inhibits sexual behavior in rat [Nature, 305, 232 (1983)]; CRFreduces sleep in rat and is thus implicated the involvement in sleepdisorder [Pharmacol. Biochem. Behav., 26, 699 (1987)]; α-helicalCRF(9-41), a peptide CRF antagonist, suppresses brain damage orelectroencephalogram disturbances due to brain ischemia or NMDA receptoractivation [TIPS, 17, 166 (1996)]; CRF elicits electroencephalogram andinduces convulsions [Brain Res., 278, 332 (1983)]; cerebrospinal CRFlevels are elevated in schizophrenic patients compared with healthyindividuals [Am. J. Psychiatry, 144(7), 873 (1987)]; CRF content incerebral cortex is reduced in Alzheimer's disease patients, Parkinson'sdisease patients and progressive supranuclear palsy patients [Neurology,37, 905 (1987)]; and CRF is reduced in the ganglia in Huntington'sdisease [Neurology, 37, 905 (1987); Brain Res., 437, 355 (1987)]. Inaddition, CRF administration has been found to enhance learning andmemory in rat [Exp. Clin. Endcrinol. Diabetes, 105, 65 (1997)].

CRF content in cerebrospinal fluid are reduced in amyotrophic lateralsclerosis patients. Oversecretion of ACTH and adrenocorticosteroids areexhibited in mice overexpressing CRF, these mice display abnormalitiessimilar to Cushing's syndrome, including muscular atrophy, alopecia andinfertility [Endocrinology, 130(6), 3378 (1992)]; cerebrospinal CRF iselevated in anorexia nervosa patients compared with healthy individuals,and plasma ACTH increase is low with administration of CRF to anorexianervosa patients; and CRF suppress feeding in experimental animals[TIPS, 17, 166 (1996)]. Moreover, α-helical CRF(9-41), a peptide CRFantagonist, improves stress-induced hypophagia in animal models [BrainRes. Bull., 17(3), 285 (1986)]; CRF has suppressed body weight gain inhereditary obese animals; a link has been suggested between low CRFlevels and obesity syndrome; and the anorexic action and the body weightloss action of serotonin reuptake inhibitors has been possibly mediatedby CRF release [TIPS, 17, 166 (1996)].

CRF acts centrally or peripherally to weaken gastric contraction andreduce gastric emptying [Annals of the New York Academy of Sciences,697, 233 (1993)]. Furthermore, reduced gastric function induced byabdominal surgery is recovered by α-helical CRF(9-41), a peptide CRFantagonist [Am. J. Physiol., 262, G616 (1992)]; and CRF promotessecretion of bicarbonate ion in the stomach, thereby lowering gastricacid secretion and suppressing cold restraint stress ulcers [Am. J.Physiol., 258, G152 (1990)]. Also, administration of CRF increasesulcers in non-restraint stress animals [Life Sci., 45, 907 (1989)]; andCRF suppresses small intestinal transit and promotes large intestinaltransit, and defecation is induced. In addition, α-helical CRF(9-41), apeptide CRF antagonist, has a inhibiting action against restraintstress-induced gastric acid secretion, reduced gastric emptying, reducedsmall intestinal transit and promoted large intestinal transit[Gastroenterology, 95, 1510 (1988)]; psychological stress in healthyindividuals increases anxiety or sensations of gas and abdominal painduring colonic distension and CRF lowers the discomfort threshold[Gastroenterol., 109, 1772 (1995); Neurogastroenterol. Mot., 8, 9(1996)]; and irritable bowel syndrome patients experience excessiveacceleration of colonic motility with CRF administration compared tohealthy individuals [Gut, 42, 845 (1998)].

Administration of CRF increases blood pressure, heart rate and bodytemperature, while α-helical CRF(9-41), a peptide CRF antagonist,suppresses stress-induced increases in blood pressure, heart rate andbody temperature [J. Physiol., 460, 221 (1993)]. CRF production isincreased locally in inflammation sites in experimental animals and inthe synovial fluid of rheumatic arthritis patients [TIPS, 17, 166(1996)]; CRF provokes degranulation of mast cells and promotes vascularpermeability [Endocrinology, 139(1), 403 (1998)]; CRF is detected inautoimmune thyroiditis patients [Am. J. Pathol., 145, 1159 (1994)];administration of CRF to experimental autoimmune encephalomyelitis ratshas notably suppressed progression of symptoms such as paralysis [J.Immunol., 158, 5751 (1997)]; and urocortin (a CRF analogue) hasincreased growth hormone secretion in a pituitary adenoma culture systemfrom an acromegalia patient [Endocri. J, 44, 627 (1997)]. Furthermore,CRF simulates secretion of cytokines such as interleukin-1 andinterleukin-2 by leukocytes [J. Neuroimmunol., 23, 256 (1989); Neurosci.Lett., 120, 151 (1990)]; and CRF administration and stress both suppressT lymphocyte proliferation and natural killer cell activity. α-helicalCRF(9-41), a peptide CRF antagonist, improves the reduced function ofthese immune cells caused by CRF administration or stress[Endocrinology, 128(3), 1329 (1991)], and breathing is notably increasedby administration of CRF [Eur. J. Pharmacol., 182, 405 (1990)]. Finally,aggravated breathing and insomnia have been observed as a result of CRFadministration to elderly patients under chronic artificial respiration[Acta Endocrinol. Copenh., 127, 200 (1992)].

The research cited above suggests that CRF antagonists may be expectedto exhibit excellent effects for treatment or prevention of depressionand depressive symptoms such as major depression, single-episodedepression, recurrent depression, depression-induced child abuse andpostpartum depression, mania, anxiety, generalized anxiety disorder,panic disorder, phobia, obsessive-compulsive disorder, posttraumaticstress disorder, Tourette's syndrome, autism, affective disorder,dysthymia, bipolar disorder, cyclothymic personality, schizophrenia,Alzheimer's disease, senile dementia of Alzheimer's type,neurodegenerative disease such as Parkinson's disease and Huntington'sdisease, multi-infarct dementia, senile dementia, anorexia nervosa,hyperphagia and other eating disorders, obesity, diabetes, alcoholdependence, pharmacophilia for drugs such as cocaine, heroin orbenzodiazepines, drug or alcohol withdrawal symptoms, sleep disorder,insomnia, migraine, stress-induced headache, muscle contraction inducedheadache, ischemic neuronal damage, excitotoxic neuronal damage, stroke,progressive supranuclear palsy, amyotrophic lateral sclerosis, multiplesclerosis, muscular spasm, chronic fatigue syndrome, psychosocialdwarfism, epilepsy, head trauma, spinal cord injury, cheirospasm,spasmodic torticollis, cervicobrachial syndrome, primary glaucoma,Meniere's syndrome, autonomic imbalance, alopecia, neuroses such ascardiac neurosis, gastric neurosis and bladder neurosis, peptic ulcer,irritable bowel syndrome, ulcerative colitis, Crohn's disease, diarrhea,constipation, postoperative ileus, stress-associated gastrointestinaldisorders and nervous vomiting, hypertension, cardiovascular disorderssuch as angina pectoris nervosa, tachycardia, congestive heart failure,hyperventilation syndrome, bronchial asthma, apneusis, sudden infantdeath syndrome, inflammatory disorders (e.g., rheumatic arthritis,osteoarthritis, lumbago, etc.), pain, allergosis (e.g., atopicdermatitis, eczema, hives, psoriasis, etc.), impotence (erectiledysfunction), menopausal disorder, fertilization disorder, infertility,cancer, HIV infection-related immune dysfunction, stress-induced immunedysfunction, hemorrhagic stress, Cushing's syndrome, thyroid functiondisorder, encephalomyelitis, acromegaly, incontinence, osteoporosis, andthe like. As examples of CRF antagonists there have been reportedpeptide CRF receptor antagonists with modifications or deletions ofportions of the amino acid sequence of human or other mammalian CRF, andsuch antagonists have shown ACTH release-inhibiting action or anxiolyticaction [Science, 224, 889 (1984); J. Pharmacol. Exp. Ther., 269, 564(1994); Brain Res. Rev., 15, 71 (1990)]. However, peptide derivativeshave low utility value as drugs from the standpoint of pharmacokineticsincluding their in vivo chemical stability, oral absorption,bioavailability and intracerebral transport.

The following nonpeptide CRF antagonists have been reported.

[1] Pyrazolotriazine compounds (WO0059907), pyrazolopyrimidine compounds(WO0059908), imidazo[1,2-a]pyrazine compounds (WO0206286, WO0262800) andimidazo[1,2-a]pyridine compounds (WO9835967, WO02062800); and

[2] Benzimidazole compounds (EP0812831), imidazopyrimidine compounds andimidazopyridine compounds (EP0994877), imidazo[4,5-c]pyrazole compounds(WO9910350), benzimidazole compounds, imidazo-pyridine compounds,imidazo-pyridazine compounds and imidazo-triazine compounds (WO0001697),1H-imidazo[4,5-d]pyridazin-7-one compounds and3H-imidazo[4,5-c]pyridin-4-one compounds (WO0039127), imidazopyrimidinecompounds and imidazopyridine compounds (WO0144248) and imidazolecompounds (WO02058704).

However, none of these are compounds having a substituted amino groupbonded at the 3-position and a substituted phenyl group bonded at the7-position of pyrazolo[1,5-a]pyridine, and no compounds are known whichexhibit CRF antagonism and have pyrazolo[1,5-a]pyridine as the skeleton,with a substituted amino group bonded at the 3-position and asubstituted phenyl group bonded at the 7-position.

The following compounds which have pyrazolo[1,5-a]pyridine structurehave also been reported: U.S. Pat. No. 5,457,200, U.S. Pat. No.4,925,849, U.S. Pat. No. 5,565,468 and U.S. Pat. No. 5,691,347.

However, none of the compounds described in these publications arementioned as exhibiting CRF receptor antagonism, antidepressive actionor antianxiety action. (For example, the compounds described in U.S.Pat. No. 5,457,200 are mentioned only in terms of their use forcolorimetry. The compounds described in U.S. Pat. No. 4,925,849 arementioned only in terms of their use as diuretics and treatment agentsfor hypertension. The compounds described in U.S. Pat. No. 5,565,468 arementioned only in regard to their angiotensin II antagonism andvasoconstrictive action. The compounds described in U.S. Pat. No.5,691,347 are described in terms of their use as treatment agents foratherosclerosis and hypercholestelemia.)

Furthermore, when the structures of the compounds described in each ofthese publications are compared, none of the compounds are compoundshaving a substituted amino group bonded at the 3-position and asubstituted phenyl group bonded at the 7-position ofpyrazolo[1,5-a]pyridine. In other words, no compounds are known whichhave a substituted amino group bonded at the 3-position and asubstituted phenyl group bonded at the 7-position ofpyrazolo[1,5-a]pyridine, as according to the present invention, andabsolutely no method is known for synthesis of such compounds.

DISCLOSURE OF INVENTION

As mentioned above, it is ardently desired to provide CRF receptorantagonists which are useful as drugs, and clinically effective agentsthat exhibit excellent CRF receptor antagonism and satisfy therequirements of pharmacological activity, dosage and safety as medicineshave not yet been discovered. It is therefore an object of the presentinvention to investigate and discover such excellent CRF receptorantagonists.

As a result of much diligent examination and research in light of thecircumstances described above, the present inventors have discoverednovel pyrazolo[1,5-a]pyridine compounds exhibiting excellent CRFreceptor antagonism.

The invention provides:<1> a compound represented by the formula:

[wherein R¹ is a group represented by the formula -G^(1z)-R^(1z)(wherein G^(1z) is a single bond, oxygen or sulfur, and R^(1z) is methylor ethyl) or methoxymethyl;R⁵ and R⁶ are each independently hydrogen, t-butoxycarbonyl or a grouprepresented by the formula —X^(6b)—X^(7b) (wherein X^(6b) is methyleneand X^(7b) is C₁₋₆ alkyl, C₃₋₈ cycloalkyl, tetrahydropyran-yl ortetrahydrofuran-yl);and two of R⁴⁰, R⁴¹ and R⁴² are C₁₋₆ alkoxy while the remaining one is agroup represented by the formula —V^(1a)—V^(2a) (wherein V^(1a) is asingle bond, —CO—, C₁₋₆ alkylene, C₂₋₆ alkenylene or C₂₋₆ alkynylene,and V^(2a) is hydrogen, hydroxyl, C₁₋₆ alkyl optionally substituted with1 to 3 substituents selected from Substituent Group B below, C₁₋₆ alkoxyoptionally substituted with 1 to 3 substituents selected fromSubstituent Group B below, a group represented by —N(R^(3c))R^(3d)(wherein R^(3c) and R^(3d) are each independently hydrogen or C₁₋₆ alkyloptionally substituted with 1 to 3 substituents selected fromSubstituent Group B below), methanesulfonyloxy, p-toluenesulfonyloxy,pyrrolidinyl, piperazinyl, piperidyl, morpholinyl, C₃₋₈ cycloalkyl,tetrahydropyran-yl or tetrahydrofuran-yl),wherein Substituent Group B is the group consisting of fluorine atom,chlorine atom, bromine atom, cyano, C₁₋₆ alkoxy, pyrrolidinyl,piperazinyl, piperidyl, morpholinyl, C₃₋₈ cycloalkyl, tetrahydropyran-yland tetrahydrofuran-yl], a salt thereof or a hydrate of the foregoing;<2> a compound according to <1>, a salt thereof or a hydrate of theforegoing, wherein R¹ is methyl, ethyl, methoxy, methylthio ormethoxymethyl;<3> a compound according to <1>, a salt thereof or a hydrate of theforegoing, wherein R⁴⁰ and R⁴² are each independently C₁₋₆ alkoxy, andR⁴¹ is a group represented by the formula:

(wherein R⁴⁴ and R⁴⁵ are each independently hydrogen, methyl or ethyl;and R⁴³ is C₁₋₆ alkyl optionally substituted with 1 to 3 substituentsselected from Substituent Group B below, wherein Substituent Group B isthe group consisting of fluorine atom, chlorine atom, bromine atom,cyano, C₁₋₆ alkoxy, pyrrolidinyl, piperazinyl, piperidyl, morpholinyl,C₃₋₈ cycloalkyl, tetrahydropyran-yl and tetrahydrofuran-yl);<4> a compound represented by the formula:

[wherein R^(5t) and R^(6t) are each independently cyclopropylmethyl,(4-tetrahydropyranyl)methyl, (3-tetrahydrofuranyl)methyl or(2-tetrahydrofuranyl)methyl;R^(1t) is methoxy, methylthio, methyl, ethyl or methoxymethyl; andR^(43t) is C₁₋₆ alkyl],a salt thereof or a hydrate of the foregoing;<5> a compound according to <4>, a salt thereof or a hydrate of theforegoing, wherein R^(43t) is methyl;<6> a compound according to <4>, a salt thereof or a hydrate of theforegoing, wherein R^(1t) is methoxy, methylthio or ethyl;<7> a compound according to <4>, a salt thereof or a hydrate of theforegoing, wherein R^(5t) is cyclopropylmethyl or(4-tetrahydropyranyl)methyl;<8> a compound according to <4>, a salt thereof or a hydrate of theforegoing, wherein R^(5t) is (4-tetrahydropyranyl)methyl;<9> a compound according to <4>, a salt thereof or a hydrate of theforegoing, wherein R^(5t) is (4-tetrahydropyranyl)methyl, and R^(6t) iscyclopropylmethyl;<10> a compound according to <1>, a salt thereof or a hydrate of theforegoing, wherein the compound isN-cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine,N-cyclopropylmethyl-N-7-[4-(ethoxymethyl)-2,6-dimethoxyphenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylamineorN-cyclopropylmethyl-N-[7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine;<11> a compound according to <1>, a salt thereof or a hydrate of theforegoing, wherein the compound isN-cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine;<12> a compound (except (i) 4-(hydroxymethyl)-2,6-dimethoxyphenylboricacid and (ii)4-(((t-butyldiphenylsilyl)oxy)methyl)-2,6-dimethoxyphenylboric acid),represented by the formula:

[wherein R⁴⁸ is hydrogen, C₁₋₆ alkyl optionally substituted with 1 to 3substituents selected from Substituent Group B below, benzyl optionallysubstituted with 1 to 3 substituents selected from Substituent Group Bbelow, 2-tetrahydropyranyl or a group represented by the formula:

(wherein R⁵¹, R⁵² and R⁵³ are each independently C₁₋₆ alkyl or phenyl);R⁴⁶ and R⁴⁷ are each independently C₁₋₆ alkyl;V^(1c) is C₁₋₆ alkylene;M is a group represented by the formula:

(wherein R^(9a) and R^(9b) are each independently hydrogen or C₁₆ alkyl,where R^(9a) and R^(9b) may bond together to form 1,2-ethylene,1,3-propylene or 2,3-dimethyl-butan-2,3-diyl), or a group represented bythe formula:

(wherein R^(9c), R^(9d) and R^(9e) are each independently C₁₋₆ alkyl);andSubstituent Group B is the group consisting of fluorine atom, chlorineatom, bromine atom, cyano, C₁₋₆ alkoxy, pyrrolidinyl, piperazinyl,piperidyl, morpholinyl, C₃₋₈ cycloalkyl, tetrahydropyranyl andtetrahydrofuranyl], a salt thereof or a hydrate of the foregoing;<13> a compound according to <12>, a salt thereof or a hydrate of theforegoing, wherein R⁴⁶ and R⁴⁷ are methyl, and V^(1c) is methylene;<14> a compound according to <12>, a salt thereof or a hydrate of theforegoing, wherein R⁴⁶ and R⁴⁷ are methyl, V^(1c) is methylene, and R⁴⁸is methyl;<15> a corticotropin-releasing factor (CRF) receptor antagonistcomprising a compound according to <1> or a salt thereof;<16> a corticotropin-releasing factor (CRF) 1 receptor antagonistcomprising a compound according to <1> or a salt thereof;<17> a therapeutic or prophylactic agent for a disease associated withcorticotropin-releasing factor (CRF), comprising a compound according to<1> or a salt thereof;<18> a therapeutic or prophylactic agent for depression, a depressivesymptom, mania, anxiety, general anxiety disorder, panic disorder,phobia, obsessive-compulsive disorder, posttraumatic stress disorder,Tourette's syndrome, autism, affective disorder, dysthymia, bipolardisorder, cyclothymic personality or schizophrenia, comprising acompound according to <1> or a salt thereof;<19> a therapeutic or prophylactic agent for peptic ulcer, irritablebowel syndrome, ulcerative colitis, Crohn's disease, diarrhea,constipation, postoperative ileus, stress-associated gastrointestinaldisorder or nervous vomiting, comprising a compound according to <1> ora salt thereof;<20> a therapeutic or prophylactic method for a disease associated withcorticotropin releasing factor (CRF), comprising administration of acompound according to <1> or a salt thereof;<21> a therapeutic or prophylactic method for depression, a depressivesymptom, mania, anxiety, general anxiety disorder, panic disorder,phobia, obsessive-compulsive disorder, posttraumatic stress disorder,Tourette's syndrome, autism, affective disorder, dysthymia, bipolardisorder, cyclothymic personality or schizophrenia, comprisingadministration of a compound according to <1> or a salt thereof;<22> a therapeutic or prophylactic method for peptic ulcer, irritablebowel syndrome, ulcerative colitis, Crohn's disease, diarrhea,constipation, postoperative ileus, stress-associated gastrointestinaldisorder or nervous vomiting, comprising administration of a compoundaccording to <1> or a salt thereof;<23> use of a compound according to <1>, a salt thereof or a hydrate ofthe foregoing for the manufacture of a medicament; and<24> use of a compound according to <1>, a salt thereof or a hydrate ofthe foregoing for the manufacture of a therapeutic agent or aprophylactic agent for a disease for which inhibition of corticotropinreleasing factor (CRF) receptor is effective.

BEST MODE FOR CARRYING OUT THE INVENTION

The symbols and terms used throughout the present specification will nowbe defined, with a more detailed description of the invention.

Several of the structural formulas given for compounds throughout thepresent specification will represent a specific isomer for convenience,but the invention is not limited to such specific isomers andencompasses all isomers and isomer mixtures, including geometricisomers, asymmetric carbon-derived optical isomers, stereoisomers andtautomers, implied by the structures of the compounds, of which anyisomer or mixture thereof may be used. The compounds of the presentinvention therefore may include those having asymmetric carbons in theirmolecules and existing as optically active forms or racemic forms, andall such compounds are encompassed by the invention withoutrestrictions. The compounds of the present invention may be crystallineor noncrystalline; there are also no restrictions on any crystallinepolymorphism of the compounds, and any crystal forms may be used aloneor in mixtures; and the compounds of the present invention alsoencompasses anhydrates, hydrates, and mixtures thereof. Metabolites ofthe compounds of the present invention, produced by degradation in vivo,are also encompassed by the claims of the invention.

The term “CRF receptor antagonist” as used throughout the presentspecification refers to a substance capable of inactivating CRFreceptors. Such substances also include those capable of attenuating orinhibiting the physiological activity of CRF.

As diseases included among “diseases associated with CRF” or “diseasesassociated with CRF receptors” according to the present specificationthere may be mentioned depression and depressive symptoms (majordepression, single-episode depression, recurrent depression,depression-induced child abuse, postpartum depression, etc.), mania,anxiety, generalized anxiety disorder, panic disorder, phobias,obsessive-compulsive disorder, posttraumatic stress disorder, Tourette'ssyndrome, autism, affective disorder, dysthymia, bipolar disorder,cyclothymic personality, schizophrenia, peptic ulcer, irritable bowelsyndrome, ulcerative colitis, Crohn's disease, diarrhea, constipation,postoperative ileus, stress-associated gastrointestinal disorders,nervous vomiting, Alzheimer's disease, senile dementia of Alzheimer'stype, neurodegenerative disease, multi-infarct dementia, seniledementia, anorexia nervosa, eating disorder, obesity, diabetes, alcoholdependence, pharmacophilia, drug withdrawal symptoms, alcohol withdrawalsymptoms, sleep disorder, insomnia, migraine, stress-induced headache,muscle contraction induced headache, ischemic neuronal damage,excitotoxic neuronal damage, stroke, progressive supranuclear palsy,amyotrophic lateral sclerosis, multiple sclerosis, muscular spasm,chronic fatigue syndrome, psychosocial dwarfism, epilepsy, head trauma,spinal cord injury, cheirospasm, spasmodic torticollis, cervicobrachialsyndrome, primary glaucoma, Meniere's syndrome, autonomic imbalance,alopecia, neurosis, hypertension, cardiovascular disorder, tachycardia,congestive heart failure, hyperventilation syndrome, bronchial asthma,apneusis, sudden infant death syndrome, inflammatory disorder, pain,allergosis, impotence, menopausal disorder, fertilization disorder,infertility, cancer, HIV infection-related immune dysfunction,stress-induced immune dysfunction, hemorrhagic stress, Cushing'ssyndrome, thyroid function disorder, encephalomyelitis, acromegaly,incontinence, osteoporosis, and the like. The compounds of the presentinvention are effective for treatment or prevention of theaforementioned diseases.

The term “neurodegenerative disease” as used throughout the presentspecification refers to either acute degenerative disease or chronicdegenerative disease, and specifically it includes, for example,neuropathies such as subarachnoid hemorrhage, acute stagecerebrovascular disorder, etc. and Alzheimer's disease, Parkinson'sdisease, Huntington's chorea, amyotrophic lateral sclerosis,spinocerebellar degeneration, etc. The term “eating disorder” as usedthroughout the present specification refers to hyperphagia, cibophobiaand the like. The term “cardiovascular disorder” as used throughout thepresent specification refers to angina pectoris nervosa and the like.The term “inflammatory disorder” as used throughout the presentspecification refers to, for example, rheumatic arthritis,osteoarthritis, lumbago and the like, and the term “allergosis” refersto, for example, atopic dermatitis, eczema, hives, psoriasis and thelike.

Throughout the present specification, “n-” signifies “normal”, “sec-”signifies “secondary” and “tert-” and “t-” both signify “tertiary”.

[Definition of R¹]

R¹ is a group represented by the formula -G^(1z)-R^(1z) (wherein G^(1z)is a single bond, oxygen or sulfur, and R^(1z) is methyl or ethyl) ormethoxymethyl, with methyl, ethyl, methoxy, methylthio, ethoxy andmethoxymethyl being preferred, ethyl, methoxy and methylthio being morepreferred, and ethyl being even more preferred.

[Definitions of R⁵ and R⁶]

R⁵ and R⁶ are each independently hydrogen, t-butoxycarbonyl or a grouprepresented by the formula —X^(6b)—X^(7b) (wherein X^(6b) is methylene;and X^(7b) is C₁₋₆ alkyl, C₃₋₈ cycloalkyl, tetrahydropyran-yl ortetrahydrofuran-yl). Preferably, R⁵ and R⁶ are each independentlyn-propyl, n-butyl, (cyclobutyl)methyl, cyclopropylmethyl,(tetrahydropyranyl)methyl or (tetrahydrofuranyl)methyl. More preferably,R⁵ and R⁶ are each independently cyclopropylmethyl,(4-tetrahydropyranyl)methyl, (3-tetrahydrofuranyl)methyl or(2-tetrahydrofuranyl)methyl. Even more preferably, R⁵ iscyclopropylmethyl or (4-tetrahydropyranyl)methyl, and most preferably R⁵is cyclopropylmethyl and R⁶ is (4-tetrahydropyranyl)methyl.

[Definitions of R⁴⁰, R⁴¹ and R⁴²]

Two of R⁴⁰, R⁴¹ and R⁴² are C₁₋₆ alkoxy while the remaining one is agroup represented by the formula —V^(1a)—V^(2a) (wherein V^(1a) is asingle bond, —CO—, C₁₋₆ alkylene, C₂₋₆ alkenylene or C₂₋₆ alkynylene;and V^(2a) is hydrogen, hydroxyl, C₁₋₆ alkyl optionally having 1-3substituents selected from Substituent Group B above, C₁₋₆ alkoxyoptionally having 1-3 substituents selected from Substituent Group Babove, a group represented by the formula —N(R^(3c))R^(3d) (whereinR^(3c) and R^(3d) are each independently hydrogen or C₁₋₆ alkyloptionally having 1-3 substituents selected from Substituent Group Babove), methanesulfonyloxy, p-toluenesulfonyloxy, pyrrolidinyl,piperazinyl, piperidyl, morpholinyl, C₃₋₈ cycloalkyl, tetrahydropyran-ylor tetrahydrofuran-yl).

Preferably, two of R⁴⁰, R⁴¹ and R⁴² are methoxy. More preferably, R⁴⁰and R⁴² are methoxy.

[Definition of R⁴³]

R⁴³ is C₁₋₆ alkyl optionally having 1-3 substituents selected fromSubstituent Group B above. Preferably, R⁴³ is methyl optionally having1-3 substituents selected from Substituent Group B above or ethyloptionally having 1-3 substituents selected from Substituent Group Babove, more preferably methyl optionally having 1-3 substituentsselected from Substituent Group B above, and even more preferablymethyl.

[Definitions of R⁴⁴ and R⁴⁵]

R⁴⁴ and R^(4s) are each independently hydrogen, methyl or ethyl.Preferably, R⁴⁴ and R⁴⁵ are each independently hydrogen or methyl, andeven more preferably R⁴⁴ and R⁴⁵ are both hydrogen.

[Definition of R^(1t)]

R^(1t) is methoxy, methylthio, methyl, ethyl or methoxymethyl. R^(1t) ispreferably methoxy, methylthio or ethyl, and more preferably ethyl.

[Definitions of R⁴⁶ and R⁴⁷]

R⁴⁶ and R⁴⁷ are each C₁₋₆ alkyl. Preferably, R⁴⁶ and R⁴⁷ are bothmethyl.

[Definition of V^(1c)]

V^(1c) is C₁₋₆ alkylene. Preferably, V^(1c) is methylene.

[Definition of M]

M is a group represented by the formula:

(wherein R^(9a) and R^(9b) are each independently hydrogen or C₁₋₆alkyl, or R^(9a) and R^(9b) bond together to form 1,2-ethylene,1,3-propylene or 2,3-dimethyl-butane-2,3-diyl), or a group representedby the formula:

(wherein R^(9c), R^(9d) and R^(9e) are each independently C₁₋₆ alkyl)

Preferably, M is a group represented by the formula:

and more preferably a group represented by the formula:

The term “pyrrolidinyl” used throughout the present specification refersto a monovalent substituent by removing a hydrogen atom frompyrrolidine, and specifically there may be mentioned 1-pyrrolidinyl,2-pyrrolidinyl or 3-pyrrolidinyl.

The term “piperazinyl” used throughout the present specification refersto a monovalent substituent by removing a hydrogen atom from piperazine,and specifically there may be mentioned 1-piperazinyl, 2-piperazinyl,3-piperazinyl or 4-piperazinyl.

The term “piperidyl” used throughout the present specification refers toa monovalent substituent by removing a hydrogen atom from piperidine,and specifically there may be mentioned 1-piperidyl, 2-piperidyl,3-piperidyl or 4-piperidyl.

The term “morpholinyl” used throughout the present specification refersto a monovalent substituent by removing a hydrogen atom from morpholine,and specifically there may be mentioned 2-morpholinyl, 3-morpholinyl or4-morpholinyl.

The term “tetrahydropyran-yl” used throughout the present specificationrefers to a monovalent substituent by removing a hydrogen atom fromtetrahydropyran, and specifically there may be mentionedtetrahydropyran-2-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl.Preferably it is tetrahydropyran-4-yl, which is represented by theformula:

The term “tetrahydrofuran-yl” used throughout the present specificationrefers to a monovalent substituent by removing a hydrogen atom fromtetrahydrofuran, and specifically there may be mentionedtetrahydrofuran-2-yl or tetrahydrofuran-3-yl. Preferably it istetrahydrofuran-3-yl, which is represented by the formula:

(4-Tetrahydropyranyl)methyl used throughout the present specificationrefers to methyl substituted with aforementioned tetrahydropyran-4-yl.

(2-Tetrahydrofuranyl)methyl used throughout the present specificationrefers to methyl substituted with aforementioned tetrahydrofuran-2-yl.

(3-Tetrahydrofuranyl)methyl used throughout the present specificationrefers to methyl substituted with aforementioned tetrahydrofuran-3-yl.

Halogen in the present specification refers to fluorine, chlorine,bromine, iodine and the like, with fluorine, chlorine or bromine beingpreferred.

C₁₋₆ alkyl in the present specification refers to linear or branchedalkyl of 1 to 6 carbon, and are preferably methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl,1-ethylpropyl, 2-ethylpropyl, n-hexyl, 1-methyl-2-ethylpropyl,1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1-propylpropyl,1-methylbutyl, 2-methylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl,2-methylpentyl, 3-methylpentyl, or the like, more preferably methyl,ethyl, n-propyl, iso-propyl or tert-butyl, and even more preferablymethyl, ethyl or iso-propyl.

C₂₋₆ alkenyl in the present specification refers to linear or branchedalkenyl of 2 to 6 carbon, and preferred examples are vinyl, allyl,1-propenyl, 2-propenyl, isopropenyl, 2-methyl-1-propenyl,3-methyl-1-propenyl, 2-methyl-2-propenyl, 3-methyl-2-propenyl,1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 1-hexenyl, 1,3-hexanedienyland 1,6-hexanedienyl.

C₂₋₆ alkynyl in the present specification refers to alkynyl of 2 to 6carbon, and preferred examples are ethynyl, 1-propynyl, 2-propynyl,1-butynyl, 2-butynyl, 3-butynyl, 3-methyl-1-propynyl,1-ethynyl-2propynyl, 2-methyl-3-propynyl, 1-pentynyl, 1-hexynyl,1,3-hexanediynyl and 1,6-hexanediynyl.

The term “C₁₋₆ alkylene” used throughout the present specificationrefers to a divalent group derived by removing another hydrogen atomfrom the aforementioned “C₁₋₆ alkyl”, and as specific examples there maybe mentioned methylene, ethylene, methylethylene, propylene,ethylethylene, 1,1-dimethylethylene, 1,2-dimethylethylene, trimethylene,1-methyltrimethylene, 1-ethyltrimethylene, 2-methyltrimethylene,1,1-dimethyltrimethylene, tetramethylene, pentamethylene andhexamethylene, preferably methylene and 1,2-ethylene, and morepreferably methylene.

The term “C₂₋₆ alkenylene” used through the present specification refersto a divalent group derived by removing another hydrogen atom from theaforementioned “C₂₋₆ alkenyl”, and as specific examples there may bementioned vinylene, propenylene, butenylene, pentenylene and hexenylene,preferably vinylene, propenylene, butenylene, pentenylene, even morepreferably vinylene, propenylene and butenylene, and even morepreferably 1,2-vinylene and 1,3-propenylene.

The term “C₂₋₆ alkynylene” used throughout the present specificationrefers to a monovalent group derived by removing another hydrogen atomfrom the aforementioned “C₂₋₆ alkynylene”, and as specific examplesthere may be mentioned ethynylene, propynylene, butynylene, pentynyleneand hexynylene, preferably ethynylene, propynylene, butynylene andpentynylene, more preferably ethynylene, propynylene and butynylene,even more preferably ethynylene and propynylene, and most preferablyethynylene.

C₃₋₈ cycloalkyl in the present specification refers to a cyclicaliphatic hydrocarbon group of 3 to 8 carbon, and as examples there maybe mentioned cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl, preferably cyclopropyl, cyclobutyl andcyclopentyl, and more preferably cyclopropyl.

C₁₋₆ alkoxy in the present specification refers to oxygen bonded withthe aforementioned “C₁₋₆ alkyl”, and as examples there may be mentionedmethoxy, ethoxy, n-propoxy, iso-propoxy, sec-propoxy, n-butoxy,iso-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, iso-pentyloxy,sec-pentyloxy, n-hexoxy, iso-hexoxy, 1,1-dimethylpropyloxy,1,2-dimethylpropoxy, 2,2-dimethylpropyloxy, 2-ethylpropoxy,1-methyl-2-ethylpropoxy, 1-ethyl-2-methylpropoxy,1,1,2-trimethylpropoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy,2,2-dimethylbutoxy, 2,3-dimethylbutyloxy, 1,3-dimethylbutyloxy,2-ethylbutoxy, 1,3-dimethylbutoxy, 2-methylpentoxy, 3-methylpentoxy andhexyloxy, preferably methoxy, ethoxy, n-propoxy, iso-propoxy,sec-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy, and morepreferably methoxy.

The phrase “optionally substituted” used throughout the presentspecification means optionally substituted with 1-3 substituentsselected from Substituent Group B above.

The phrase “a compound . . . , a salt thereof or a hydrate of theforegoing” used throughout the present specification refers to (i)compound (I), (ii) a salt of compound (I), (iii) a hydrate of compound(I) or (iv) a hydrate of a salt of compound (I), and it is preferably(i) compound (I) or (ii) a salt of compound (I), and more preferably asalt of compound (I).

The term “hydrate” used throughout the present specification refers tothe state of a compound hydrated (solvated) with water or the state of asalt of the compound hydrated (solvated) with water. Preferably ahydrate is formed in an appropriate ratio of 0.1 to 8 molecules of waterto 1 molecule of a compound or salt of the compound, and more preferablya hydrate is formed in an appropriate ratio of 0.3 to 3 molecules ofwater to 1 molecule of a compound.

The salts of compound (I) of the present invention are not particularlyrestricted so long as they are salts formed with the compounds of theinvention, and for example, there may be mentioned salts with inorganicacids, salts with organic acids and salts with acidic amino acids, amongwhich pharmacologically acceptable salts are preferred. The acids mayform salts at appropriate ratios of 0.1-5 molecules to 1 molecule of thecompound.

As preferred examples of salts with inorganic acids there may bementioned salts of hydrochloric acid, hydrobromic acid, sulfuric acid,nitric acid, phosphoric acid and the like, and as preferred examples ofsalts with organic acids there may be mentioned salts of acetic acid,succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid,lactic acid, stearic acid, benzoic acid, benzenesulfonic acid,ethanesulfonic acid, methanesulfonic acid, tosylic acid(p-toluenesulfonic acid) and the like.

As preferred examples of salts with acidic amino acids there may bementioned salts with aspartic acid, glutamic acid and the like.

As preferred examples of salts of compound (I) of the invention theremay be mentioned salts with hydrochloric acid, sulfuric acid,benzenesulfonic acid, ethanesulfonic acid, methanesulfonic acid, tosylicacid or hydrobromic acid, and as more preferred examples there may bementioned salts with tosylic acid.

The compounds (except (i) 4-(hydroxymethyl)-2,6-dimethoxyphenylboricacid and (ii)4-(((t-butyldiphenylsilyl)oxy)methyl)-2,6-dimethoxyphenylboric acid)represented by the following formula, salts thereof and hydrates of theforegoing are highly useful as synthesis intermediates for compound (I)according to the invention.

[wherein R⁴⁸ is hydrogen, C₁₋₆ alkyl optionally having 1-3 substituentsselected from Substituent Group B below, benzyl optionally having 1-3substituents selected from Substituent Group B below,2-tetrahydropyranyl or a group represented by the formula:

(wherein R⁵¹, R⁵² and R⁵³ are each independently C₁₋₆ alkyl or phenyl);R⁴⁶ and R⁴⁷ are each independently C₁₋₆ alkyl; V^(1c) is C₁₋₆ alkylene;M is a group represented by the formula:

(wherein R^(9a) and R^(9b) are each independently hydrogen or C₁₋₆alkyl, or R^(9a) and R^(9b) bond together to form 1,2-ethylene,1,3-propylene or 2,3-dimethyl-butane-2,3-diyl), or a group representedby the formula:

(wherein R^(9c), R^(9d) and R^(9e) are each independently C₁₋₆ alkyl),wherein Substituent Group B is the group consisting of fluorine atom,chlorine atom, bromine atom, cyano, C₁₋₆ alkoxy, pyrrolidinyl,piperazinyl, piperidyl, morpholinyl, C₃₋₈ cycloalkyl, tetrahydropyran-yland tetrahydrofuran-yl].

The following compounds, salts thereof and hydrates of the foregoing arehighly useful as synthesis intermediates for compound (I) according tothe invention.

[1] Compounds according to compound (I) wherein —NR⁵R⁶ is:

[2] Compounds according to compound (I) wherein V^(2a) is a grouprepresented by the formula:

(wherein R⁵¹, R⁵² and R⁵³ are each independently C₁₋₆ alkyl or phenyl),methanesulfonyloxy or p-toluenesulfonyloxy.

Representative production schemes for the compounds represented byformula (I) above according to the invention will now be described. Inthe production schemes indicated below, R¹, R⁵, R⁶, R^(9a), R^(9b),R^(9c), R^(9d), R^(9e), R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷, R⁴⁸ and M have the samerespective definitions given above, X is halogen (e.g., fluorine,chlorine, bromine or iodine), Ar is phenyl optionally substituted with1-3 groups represented by the formula —V^(1a)—V^(2a) (where V^(1a) andV^(2a) have the same respective definitions given above), R^(1c) andR^(1d) are each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl or C₃₋₈cycloalkyl (each of the foregoing groups are optionally substituted),R^(ca) is optionally substituted C₁₋₆ alkyl or optionally substitutedbenzyl, X′ is bromine, iodine or hydrogen, A is nitroso or nitro, agroup represented by Prot^(N) is an amino-protecting group, a grouprepresented by Prot^(O) is a hydroxyl-protecting group, B is Ar or X[wherein Ar and X have the same respective definitions given above], Levis a leaving group such as X [wherein X has the same definition givenabove] or sulfonate (e.g., p-toluenesulfonyloxy or methanesulfonyloxy),R^(11a), R^(11b), R^(11c) and R^(11d) are each C₁₋₆ alkyl, C₃₋₈cycloalkyl, C₃₋₈ cycloalkyl-C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl,with R^(11b) and R^(11c) optionally bonding together to form a 4- to8-membered ring and the 4- to 8-membered ring being a substituentoptionally containing multiple N, O or S atoms in the ring, and n is aninteger of 1-6. The term “room temperature” used hereunder refers to atemperature in the range of 10 to 40° C.

Step 1-A: A 2-halogenopyridine derivative represented by formula (1) maybe reacted with an acetylene derivative in the presence of a palladiumcatalyst and copper (I) iodide, in the presence of a base and either ina solvent or without a solvent, at a temperature of 0° C. to 250° C., toafford an acetylene derivative (2). The solvent used will differdepending on the starting materials, reagents, etc. and is notparticularly restricted so long as it dissolves the starting materialsto some degree without inhibiting the reaction, and preferably there maybe mentioned toluene, xylene, anisole, N,N-dimethylformamide,1,2-dimethoxyethane, tetrahydrofuran, dioxane, n-butanol, ethanol,methanol, 1-methyl-2-pyrrolidinone and water, which may be used eitheralone or as a mixed solvent. The base used will differ depending on thestarting materials, solvents, etc. and is not particularly restricted solong as it does not inhibit the reaction, and preferably there may bementioned potassium carbonate, sodium carbonate, cesium fluoride,potassium fluoride, sodium hydrogencarbonate, triethylamine anddiethylamine. These bases may also be used as a solvent. Specificpalladium or nickel catalysts will differ depending on the startingmaterials, solvents, etc. and are not particularly restricted so long asthey do not inhibit the reaction, and preferably there may be mentionedtetrakis(triphenylphosphine)palladium(0), palladium(II)acetate/triphenylphosphine, palladium(II) chloride,tris(dibenzylideneacetone)dipalladium(0)/tri-tert-butylphosphine,dichloro[1,1′-bis(diphenylphosphine)-ferrocene]palladium(0),[1,2-bis(diphenylphosphino)ethane] dichloronickel(II) and[1,3-bis(diphenylphosphino)propane] dichloronickel(II). Preferably, thepalladium catalyst is used at 0.001 to 0.2 equivalent, the acetylenederivative at 1 to 20 equivalents and the base at 1 to 20 equivalents oras the solvent.

Step 1-B: An acetylene derivative represented by formula (2) may bereacted with an N-aminating agent (for example, hydroxylamineO-sulfonate or O-mesitylenesulfonylhydroxyamine) at −50° C. to 40° C.,either in a solvent or without a solvent, and the resultingN-aminopyridinium salt may be isolated through a filter or the like orused directly in the system for reaction in the presence or in theabsence of a base at 0° C. to 250° C. to afford a cyclized compoundrepresented by formula (3). The solvent used will differ depending onthe starting materials, reagents, etc. and is not particularlyrestricted so long as it dissolves the starting materials to some degreewithout inhibiting the reaction, and preferably there may be mentionedtoluene, xylene, anisole, N,N-dimethylformamide, 1,2-dimethoxyethane,tetrahydrofuran, dioxane, n-butanol, ethanol, methanol and1-methyl-2-pyrrolidinone, which may be used alone or as a mixed solvent.The base used will differ depending on the starting materials, solvents,etc. and is not particularly restricted so long as it does not inhibitthe reaction, and preferably there may be mentioned potassium carbonate,sodium carbonate, cesium fluoride, potassium fluoride, sodiumhydrogencarbonate, triethylamine, sodium methoxide, sodium ethoxide,sodium tert-butoxide and potassium tert-butoxide. In this case, theN-aminating agent is preferably used at 1 to 3 equivalents and the baseat 1 to 5 equivalents.

Step 2-A: A 2-pyridylacetic acid ester represented by formula (4) andhydroxylamine-O-sulfonate (5) may be reacted in a solvent in thepresence or in the absence of a base, to afford2-hydroxypyrazolo[1,5-a]pyridine represented by formula (6). Thereaction temperature will usually be 0° C. to 100° C. The solvent usedwill differ depending on the starting materials, reagents, etc. and isnot particularly restricted so long as it dissolves the startingmaterials to some degree without inhibiting the reaction, and preferablythere may be mentioned acetone, acetic acid, methanol, ethanol andwater, which may be used alone or as a mixed solvent.Hydroxylamine-O-sulfonate is preferably used at 0.1 to 2 equivalents andthe base at 1 to 3 equivalents.

Step 2-B: 2-Hydroxypyrazolo[1,5-a]pyridine represented by formula (6)and an alkylating agent may be reacted in a solvent or without asolvent, in the presence or in the absence of a base, to afford aderivative represented by formula (7). The reaction temperature willusually be 0° C. to 100° C. The solvent used will differ depending onthe starting materials, reagents, etc. and is not particularlyrestricted so long as it dissolves the starting materials to some degreewithout inhibiting the reaction, and preferably there may be mentionedacetone, methanol, ethanol and water, which may be used alone or as amixed solvent. As alkylating agents there may be mentioneddimethylsulfuric acid, diethylsulfuric acid, alkyl halides, diazomethaneand trimethylsilyldiazomethane. The base used will differ depending onthe starting materials, solvents, etc. and is not particularlyrestricted so long as it does not inhibit the reaction, and preferablythere may be mentioned potassium carbonate, sodium carbonate, cesiumfluoride, potassium fluoride, sodium hydrogencarbonate, triethylamine,diethylamine, sodium methoxide, sodium ethoxide and potassiumtert-butoxide. The alkylating agent is preferably used at 1 to 3equivalents and the base at 1 to 15 equivalents.

Step 3-A: A pyrazolo[1,5-a]pyridine derivative (compound (3) inProduction Scheme 1 or compound (7) in Production Scheme 2, etc.), andan alkyllithium reagent (for example, n-butyllithium, sec-butyllithium,tert-butyllithium, etc.) may be reacted in an inert solvent and thenfurther reacted with a halogenating agent, to afford apyrazolo[1,5-a]pyridine derivative represented by formula (9) having ahalogen introduced at the 7-position. The reaction temperature willusually be −100° C. to 40° C. The halogenating agent used will differdepending on the starting materials, solvents, etc. and is notparticularly restricted so long as it does not inhibit the reaction, andpreferably there may be mentioned bromine, iodine, N-chlorosuccinimide,N-bromosuccinimide, N-iodosuccinimide, hexachloroethane,1,2-dibromoethane, 1,2-dibromo-1,1,2,2-tetrachloroethane,1,2-diiodo-ethane or the like. The solvent used will differ depending onthe starting materials, reagents, etc. and is not particularlyrestricted so long as it dissolves the starting materials to some degreewithout inhibiting the reaction, and preferably there may be mentionedhexane, pentane, tetrahydrofuran and diethyl ether, which may be usedalone or as a mixed solvent. The alkyllithium reagent is preferably usedat 1 to 2 equivalents and the halogenating agent at 1 to 3 equivalents.

Step 3-B: A pyrazolo[1,5-a]pyridine derivative represented by formula(9) and a nitrating agent may be reacted either in a solvent or withouta solvent to afford a 3-nitropyrazolo[1,5-a]pyridine derivativerepresented by formula (10). The reaction temperature will usually be−70° C. to 200° C. The nitrating agent used will differ depending on thestarting materials, solvent, etc. and is not particularly restricted solong as it does not inhibit the reaction, and preferably there may bementioned copper nitrate trihydrate, nitric acid, fuming nitric acid,sodium nitrate, nitronium tetrafluoroborate, ammonium nitrate, and thelike. The solvent used will differ depending on the starting materials,reagents, etc. and is not particularly restricted so long as itdissolves the starting materials to some degree without inhibiting thereaction, and preferably there may be mentioned acetic anhydride, aceticacid, sulfuric acid, trifluoroacetic anhydride, trifluoroacetic acid,acetonitrile, 1,2-dimethoxyethane and tetrahydrofuran, which may be usedalone or as a mixed solvent. The nitrating agent is preferably used at 1to 2 equivalents.

Alternatively, a pyrazolo[1,5-a]pyridine derivative (9) and anitrosating agent such as sodium nitrite may be reacted either in asolvent or without a solvent to afford a3-nitrosopyrazolo[1,5-a]pyridine derivative represented by formula (10).The reaction temperature will usually be −40° C. to 100° C. Thenitrosating agent used will differ depending on the starting materials,solvents, etc. and is not particularly restricted so long as it does notinhibit the reaction, and preferably there may be mentioned sodiumnitrite, isoamyl nitrite and the like. The solvent used will differdepending on the starting materials, reagents, etc. and is notparticularly restricted so long as it dissolves the starting materialsto some degree without inhibiting the reaction, and preferably there maybe mentioned acetic anhydride, acetic acid, hydrochloric acid, sulfuricacid, trifluoroacetic anhydride, trifluoroacetic acid, acetonitrile,1,2-dimethoxyethane, water and ethanol, which may be used alone or as amixed solvent. The nitrosating agent is preferably used at 1 to 2equivalents.

Step 3-C: A nitro derivative or nitroso derivative represented byformula (10) and a metal (powder) may be reacted in the presence or inthe absence of an acid, either in a solvent or without a solvent, toafford a reduced compound, 3-aminopyrazolo[1,5-a]pyridine derivative(11). The reaction temperature will usually be −10° C. to 150° C. Themetal (powder) used will differ depending on the starting materials,solvents, etc. and is not particularly restricted so long as it does notinhibit the reaction, and preferably there may be mentioned zinc, iron,tin(II) chloride, nickel(II) chloride and the like. The acid used willdiffer depending on the starting materials, solvents, etc. and is notparticularly restricted so long as it does not inhibit the reaction, andpreferably there may be mentioned acetic acid, hydrochloric acid,sulfuric acid, and the like. The solvent used will differ depending onthe starting materials, reagents, etc. and is not particularlyrestricted so long as it dissolves the starting materials to some degreewithout inhibiting the reaction, and preferably there may be mentionedmethanol, ethanol, n-butanol, water and the like, which may be usedalone or as a mixed solvent. The metal (powder) is preferably used at 1to 10 equivalents.

Alternatively, a nitro derivative or nitroso derivative represented byformula (10) may be subjected to hydrogen addition reaction in an inertsolvent under a hydrogen atmosphere, in the presence or in the absenceof an acid and using a metal catalyst such as Pd—C, to afford a reducedcompound, 3-aminopyrazolo[1,5-a]pyridine derivative (11). The pressureof the hydrogen used will usually be 1 to 100 atmospheres and thereaction temperature usually 0° C. to 200° C. The acid and metalcatalyst used will differ depending on the starting materials, solvents,etc. and are not particularly restricted so long as they do not inhibitthe reaction, and as preferred acids there may be mentioned acetic acid,trifluoroacetic acid and hydrochloric acid, and as preferred metalcatalysts there may be mentioned Pd—C, PtO₂, Pt—C and Raney-Ni. Thesolvent used will differ depending on the starting materials, reagents,etc. and is not particularly restricted so long as it dissolves thestarting materials to some degree without inhibiting the reaction, andpreferably there may be mentioned methanol, ethanol, propanol, butanol,tetrahydrofuran, 1,4-dioxane, ethyl acetate, acetone andN,N-dimethylformamide, which may be used alone or as a mixed solvent. Inthis reaction, the 3-aminopyrazolo[1,5-a]pyridine derivative (11) mayalso be obtained by reaction generating hydrogen by heating ammoniumformate, etc. in a solvent such as methanol, in the presence of a metalcatalyst. The metal catalyst is preferably used at 5 to 100 wt %.

Step 3-D: A 3-aminopyrazolo[1,5-a]pyridine derivative represented byformula (11) and a protecting reagent for amino groups (for example,di-tert-butyl dicarbonate) may be reacted to afford a3-aminopyrazolo[1,5-a]pyridine derivative (12) having the amino group at3-position protected by carbamate (for example, tert-butoxycarbonyl).The reaction may be conducted either in a solvent or without a solventand in the presence or in the absence of a base. The reactiontemperature will usually be −70° C. to 150° C. The solvent used willdiffer depending on the starting materials, reagents, etc. and is notparticularly restricted so long as it dissolves the starting materialsto some degree without inhibiting the reaction, and preferably there maybe mentioned tetrahydrofuran, diethyl ether, 1,4-dioxane,dichloromethane, 1,2-dichloroethane, chloroform andN,N-dimethylformamide, which may be used alone or as a mixed solvent.The base used will differ depending on the starting materials, solvents,etc. and is not particularly restricted so long as it does not inhibitthe reaction, and preferably there may be mentioned triethylamine,pyridine, diisopropylethylamine, sodium hydride, potassium carbonate,sodium carbonate, cesium carbonate, sodium hydrogencarbonate,4-(dimethylamino)pyridine and sodium bis(trimethylsilyl)amide. Aspreferred examples of protecting groups to be used (“Prot^(N)” in thisscheme) there may be mentioned tert-butoxycarbonyl (Boc), as well as9-fluorenylmethoxycarbonyl (Fmoc), 2,2,2-trichloroethoxycarbonyl (Troc),and the like, whereby the amino group at 3-position is protected underreaction conditions employing reagents and solvents suitable for theprotecting group. The protecting reagent for amino groups is preferablyused at 1 to 3 equivalents and the base at 1 to 5 equivalents.

Step 4-A: A 1-aminopyridinium salt derivative represented by formula(13) and a 1,1-bis(alkylthio)-2-nitroethylene derivative represented byformula (14) may be reacted in the presence or in the absence of a base,either in a solvent or without a solvent, to afford a3-nitropyrazolo[1,5-a]pyridine derivative represented by formula (15)(Reference: Heterocycles, 1977, 6, 379). The reaction temperature willusually be 0° C. to 200° C. The solvent used will differ depending onthe starting materials, reagents, etc. and is not particularlyrestricted so long as it dissolves the starting materials to some degreewithout inhibiting the reaction, and preferably there may be mentionedethanol, methanol, 1,2-dimethoxyethane and tetrahydrofuran, which may beused alone or as a mixed solvent. The base used will differ depending onthe starting materials, reagents, etc. and is not particularlyrestricted so long as it does not inhibit the reaction, and preferablythere may be mentioned triethylamine, diisopropylethylamine,4-(dimethylamino)pyridine, sodium bis(trimethylsilyl)amide, and thelike. The 1,1-bis(alkylthio)-2-nitroethylene derivative is preferablyused at 1 to 2 equivalents and the base at 1 to 5 equivalents.

Step 4-B: A 3-nitropyrazolo[1,5-a]pyridine derivative represented byformula (15) may be reacted in the same manner as Step 3-C in ProductionScheme 3 above to afford a 3-aminopyrazolo[1,5-a]pyridine derivative(16).

Step 4-C: A 3-aminopyrazolo[1,5-a]pyridine derivative represented byformula (16) may be reacted in the same manner as Step 3-D in ProductionScheme 3 above to afford an amino-protected3-aminopyrazolo[1,5-a]pyridine derivative (17).

Step 4-D: An amino-protected 3-aminopyrazolo[1,5-a]pyridine derivativerepresented by formula (17) may be reacted in the same manner as Step3-A in Production Scheme 3 above to afford a pyrazolo[1,5-a]pyridinederivative (12′) having halogen introduced at the 7-position.

Step 5-A: A 3-aminopyrazolo[1,5-a]pyridine derivative (12) having theamino group protected with Prot^(N) may be reacted with an alkylatingagent (for example, an optionally substituted alkyl halide or the like)to afford a pyrazolo[1,5-a]pyridine derivative represented by formula(18) having a substituent introduced at the amino group. The reactionmay be conducted in a solvent or without a solvent, and in the presenceor in the absence of a base. The reaction temperature will usually be−70° C. to 200° C. The solvent used will differ depending on thestarting materials, reagents, etc. and is not particularly restricted solong as it dissolves the starting materials to some degree withoutinhibiting the reaction, and preferably there may be mentioneddichloromethane, acetone, tetrahydrofuran, diethyl ether,N,N-dimethylformamide and dimethylsulfoxide, which may be used alone oras a mixed solvent. The base used will differ depending on the startingmaterials, solvents, etc. and is not particularly restricted so long asit does not inhibit the reaction, and preferably there may be mentionedsodium hydride, potassium hydride, potassium carbonate, sodiumcarbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, andthe like. The alkylating agent is preferably used at 1 to 3 equivalentsand the base at 1 to 5 equivalents.

Step 5-B: A 3-aminopyrazolo[1,5-a]pyridine derivative represented byformula (18) may be subjected to deprotection reaction to afford adeprotected pyrazolo[1,5-a]pyridine derivative (19). The reaction may beconducted in the presence or in the absence of a deprotecting reagent.The reaction temperature will usually be −70° C. to 200° C. Thedeprotecting reagent used will differ depending on the startingmaterials, solvents, etc. and is not particularly restricted so long asit does not inhibit the reaction, and preferably there may be mentionedhydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonicacid, iodotrimethylsilane, aluminum(III) chloride, trimethylsilyltriflate, and the like. When a group other than tert-butoxycarbonyl(Boc) is used as the protecting group (for example, Fmoc, Troc, etc.),the deprotection is carried out by a reaction using a reagent suitablefor the protecting group. The reaction may be conducted either in asolvent or without a solvent; when it is conducted in a solvent, thesolvent used will differ depending on the starting materials, reagents,etc. and is not particularly restricted so long as it dissolves thestarting materials to some degree without inhibiting the reaction, andpreferably there may be mentioned ethyl acetate, tetrahydrofuran,diethyl ether, 1,4-dioxane, acetonitrile, dichloromethane, chloroform,nitromethane, phenol, anisole and thiophenol, which may be used alone oras a mixed solvent. The deprotecting reagent is preferably used at 1 to30 equivalents.

Step 5-C: A pyrazolo[1,5-a]pyridine derivative represented by formula(19) may be reacted with a carbonyl derivative (for example,diethylketone), an aldehyde derivative (for example, propionaldehyde) ora carbonyl equivalent (for example,((1-ethoxycyclopropyl)oxy)trimethylsilane or an acetal-protectedsubstituent) in the presence of a reducing agent to afford apyrazolo[1,5-a]pyridine derivative represented by formula (20). Thereaction temperature will usually be −10° C. to 150° C. The reaction maybe conducted in the presence or in the absence of an acid, in a solventor without a solvent, and in the presence or in the absence of aninorganic salt. The solvent used will differ depending on the startingmaterials, reagents, etc. and is not particularly restricted so long asit dissolves the starting materials to some degree without inhibitingthe reaction, and preferably there may be mentioned tetrahydrofuran,diethyl ether, 1,2-dichloroethane, dichloromethane, chloroform,acetonitrile, ethanol, methanol and water, which may be used alone or asa mixed solvent. The acid, inorganic salt and reducing agent used willdiffer depending on the starting materials, solvent, etc. and are notparticularly restricted so long as they do not inhibit the reaction, andpreferably there may be mentioned, as acids, acetic acid, sulfuric acidand the like, as inorganic salts, sodium sulfate and the like, and asreducing agents, sodium triacetoxyborohydride, sodium borohydride,sodium cyanotrihydroborate, and the like. The carbonyl and aldehydederivatives (including equivalents) are preferably used at 1 to 20equivalents, the reducing agent at 1 to 5 equivalents and the inorganicsalt at 1 to 30 equivalents.

Alternatively, a pyrazolo[1,5-a]pyridine derivative (19) and anacylating reagent may be reacted in the presence or in the absence of abase, in a solvent or without a solvent, to afford apyrazolo[1,5-a]pyridine derivative (20) having the amino group acylated.The reaction temperature will usually be −20° C. to 150° C. The solventused will differ depending on the starting materials, reagents, etc. andis not particularly restricted so long as it dissolves the startingmaterials to some degree without inhibiting the reaction, and preferablythere may be mentioned tetrahydrofuran, diethyl ether,1,2-dichloroethane, dichloromethane, acetonitrile, ethanol, methanol andwater, which may be used alone or as a mixed solvent. The base used willdiffer depending on the starting materials, solvents, etc. and is notparticularly restricted so long as it does not inhibit the reaction, andpreferably there may be mentioned triethylamine, pyridine,diisopropylethylamine, N,N-diisopropylethylamine,4-(dimethylamino)pyridine, sodium carbonate, potassium carbonate, sodiumhydroxide, potassium hydroxide and the like. The acylating agent ispreferably used at 1 to 3 equivalents and the base at 1 to 20equivalents.

Step 5-D: A 3-aminopyrazolo[1,5-a]pyridine derivative represented byformula (11) may be reacted with a carbonyl derivative (for example,diethylketone) or an aldehyde derivative (for example, propionaldehyde)in the presence of a reducing agent such as sodium triacetoxyborohydrideto afford a pyrazolo[1,5-a]pyridine derivative represented by formula(19) or formula (20). Depending on the number of moles of the carbonylderivative or aldehyde derivative used and the reaction time, it ispossible to obtain either a monosubstituted pyrazolo[1,5-a]pyridinederivative represented by formula (19) or a disubstitutedpyrazolo[1,5-a]pyridine derivative represented by formula (20). Thereaction may be conducted in the presence or in the absence of an acid,in a solvent or without a solvent, and in the presence or in the absenceof an inorganic salt. The reaction temperature will usually be −10° C.to 150° C. The solvent used will differ depending on the startingmaterials, reagents, etc. and is not particularly restricted so long asit dissolves the starting materials to some degree without inhibitingthe reaction, and preferably there may be mentioned tetrahydrofuran,diethyl ether, 1,2-dichloroethane, dichloromethane, chloroform,acetonitrile and water, which may be used alone or as a mixed solvent.The acid, inorganic salt and reducing agent used will differ dependingon the starting materials, solvents, etc. and are not particularlyrestricted so long as they do not inhibit the reaction, and preferablythere may be mentioned, as acids, acetic acid, sulfuric acid and thelike, as inorganic salts, sodium sulfate and the like, and as reducingagents, sodium triacetoxyborohydride, sodium borohydride, sodiumcyanoborohydride, and the like. The carbonyl or aldehyde derivative ispreferably used at 1 to 20 equivalents, the reducing agent at 1 to 5equivalents and the inorganic salt at 1 to 30 equivalents.

Step 5-E: A pyrazolo[1,5-a]pyridine derivative represented by formula(20) may be reacted using a metal aryl reagent or metal heteroarylreagent and a transition metal catalyst, in the presence or in theabsence of a base and in a solvent or without a solvent, to afford apyrazolo[1,5-a]pyridine derivative (I) substituted with an aryl group orheteroaryl group at the 7-position. The reaction temperature willusually be 0° C. to 200° C. Commonly employed combinations of reagentsand catalysts include arylboric acid compound/palladium catalysts(Suzuki reaction; N. Miyaura, A. Suzuki, Chemical Reviews 1995, 95,2457), aryl trialkyltin compound/palladium catalysts (Stille reaction;T. N. Mitchell, Synthesis 1992, 803), arylzinc compound/palladiumcatalysts and aryl Grignard compound/nickel catalysts. The specificpalladium and nickel catalyst used will differ depending on the startingmaterials, solvents, etc. and are not particularly restricted so long asthey do not inhibit the reaction, and preferably there may be mentionedtetrakis(triphenylphosphine)palladium(0), palladium(II)acetate/triphenylphosphine, palladium(II) chloride,tris(dibenzylideneacetone)dipalladium(0)/tri-tert-butylphosphine,dichloro[1,1′-bis(diphenylphosphine)-ferrocene]palladium(0),[1,2-bis(diphenylphosphino)ethane]dichloronickel(II),[1,3-bis(diphenylphosphino)propane]dichloronickel(II), and the like. Thesolvent used will differ depending on the starting materials, reagents,etc. and is not particularly restricted so long as it dissolves thestarting materials to some degree without inhibiting the reaction, andpreferably there may be mentioned toluene, xylene, mesitylene, anisole,N,N-dimethylformamide, 1,2-dimethoxyethane, tetrahydrofuran,1,4-dioxane, n-butanol, ethanol, methanol, 1-methyl-2-pyrrolidinone andwater, which may be used alone or as a mixed solvent. The base used willdiffer depending on the starting materials, solvent, etc. and is notparticularly restricted so long as it does not inhibit the reaction, andpreferably there may be mentioned potassium carbonate, sodium carbonate,barium hydroxide, cesium fluoride, potassium fluoride, sodiumhydrogencarbonate, triethylamine, and the like. The metal aryl reagentor metal heteroaryl reagent is preferably used at 1 to 2 equivalents,the transition metal catalyst at 0.001 to 0.2 equivalent and the base at1 to 5 equivalents.

Step 6-A: A pyrazolo[1,5-a]pyridine derivative represented by formula(12) having the amino group at 3-position protected may be reacted inthe same manner as Step 5-E in Production Scheme 5 above to afford apyrazolo[1,5-a]pyridine derivative (21) having an Ar group introduced atthe 7-position.

Step 6-B: A pyrazolo[1,5-a]pyridine derivative represented by formula(21) may be reacted in the same manner as Step 5-A in Production Scheme5 above to afford a pyrazolo[1,5-a]pyridine derivative represented byformula (22).

Step 6-C: A pyrazolo[1,5-a]pyridine derivative represented by formula(21) or (22) may be reacted in the same manner as Step 5-B in ProductionScheme 5 above to afford a deprotected pyrazolo[1,5-a]pyridinederivative (23) or (24), respectively.

Step 6-D: A pyrazolo[1,5-a]pyridine derivative represented by formula(23) may be reacted in the same manner as Step 5-D in Production Scheme5 above to afford a pyrazolo[1,5-a]pyridine derivative represented byformula (24) or (I), depending on the reaction conditions, etc.

Step 6-E: A pyrazolo[1,5-a]pyridine derivative represented by formula(24) may be reacted in the same manner as Step 5-C in Production Scheme5 above to afford a pyrazolo[1,5-a]pyridine derivative represented byformula (I).

Step 7-A: A 3-nitropyrazolo[1,5-a]pyridine derivative or3-nitrosopyrazolo[1,5-a]pyridine derivative represented by formula (10′)may be reacted in the same manner as Step 5-E in Production Scheme 5above to afford a pyrazolo[1,5-a]pyridine derivative (25) having an Argroup substituted at the 7-position.

Step 7-B: A 3-nitropyrazolo[1,5-a]pyridine derivative or3-nitrosopyrazolo[1,5-a]pyridine derivative represented by formula (25)may be reacted in the same manner as Step 3-C in Production Scheme 3above to afford a reduced compound, a pyrazolo[1,5-a]pyridine derivative(26).

Step 7-C: A 3-nitropyrazolo[1,5-a]pyridine derivative or3-nitrosopyrazolo[1,5-a]pyridine derivative represented by formula (26)may be reacted in the same manner as Step 3-D in Production Scheme 3above to afford a pyrazolo[1,5-a]pyridine derivative (21) having theamino group at 3-position protected.

Step 8-A: A carboxylic acid derivative represented by formula (27) andan azidation agent (for example, diphenylphosphoryl azide (DPPA) orsodium azide) may be reacted either in a solvent or without a solventand in the presence or in the absence of a base, at a temperature of−70° C. to 250° C., to produce an acid azide derivative, and the acidazide derivative subsequently heated at 40° C. to 250° C. forrearrangement reaction such as Curtius rearrangement to generate anisocyanate in the system, and reaction then conducted with tert-butanolor the like, to afford a 3-aminopyrazolo[1,5-a]pyridine derivative (12)or (21) protected with a carbamate group such as tert-butoxycarbonyl(Boc). The solvent used will differ depending on the starting materials,reagents, etc. and is not particularly restricted so long as itdissolves the starting materials to some degree without inhibiting thereaction, and preferably there may be mentioned toluene, xylene,diphenyl ether, tert-butanol, tetrahydrofuran, dioxane, acetonitrile andN,N-dimethylformamide, which may be used alone or as a mixed solvent.The base used will differ depending on the starting materials, solvents,etc. and is not particularly restricted so long as it does not inhibitthe reaction, and preferably there may be mentioned triethylamine,diisopropylethylamine, 4-(dimethylamino)pyridine, pyridine, and thelike. As an alternative method, the aforementioned acid azide derivativemay be synthesized by converting the carboxylic acid derivative (27) toan acid chloride or mixed acid anhydride and then reacting it with anazidation agent (for example, sodium azide, trimethylsilyl azide, etc.).As another alternative method, the target compound (12) or (21) may beobtained by Hofmann rearrangement or Schmidt rearrangement. Theazidation agent is preferably used at 1 to 3 equivalents, the base at 1to 5 equivalents, and the tert-butanol either at 1 to 50 equivalents oras the solvent.

Step 9-A: A sulfide derivative represented by formula (I^(s)) may beoxidized using an oxidizing agent such as m-chloroperbenzoic acid eitherin a solvent or without a solvent, to afford a sulfoxide derivative(I^(s1)). The reaction temperature will usually be −70° C. to 150° C.The solvent used will differ depending on the starting materials,reagents, etc. and is not particularly restricted so long as itdissolves the starting materials to some degree without inhibiting thereaction, and preferably there may be mentioned acetone, acetic acid,trifluoroacetic acid, dichloromethane, chloroform, toluene,nitromethane, methanol, ethanol and water, which may be used alone or asa mixed solvent. As oxidizing agents to be used there may be mentionedm-chloroperbenzoic acid, trifluoroperacetic acid,bis(trimethylsilyl)peracids, sodium periodate, dinitrogen tetraoxide,acid mixture of nitric acid-sulfuric acid, chromic acid, and the like.The oxidizing agent is preferably used at 1 to 2 equivalents.

Step 9-B: A sulfoxide derivative (I^(s1)) may be oxidized using anoxidizing agent such as m-chloroperbenzoic acid either in a solvent orwithout a solvent, to afford a sulfone derivative (I^(s2)). The reactiontemperature will usually be −70° C. to 150° C. The solvent used willdiffer depending on the starting materials, reagents, etc. and is notparticularly restricted so long as it dissolves the starting materialsto some degree without inhibiting the reaction, and preferably there maybe mentioned acetone, acetic acid, trifluoroacetic acid,dichloromethane, chloroform, toluene, methanol, ethanol and water, whichmay be used alone or as a mixed solvent. As oxidizing agents to be usedthere may be mentioned m-chloroperbenzoic acid, chromic acid, osmiumtetraoxide, potassium permanganate, and the like. The oxidizing agent ispreferably used at 1 to 2 equivalents.

Step 10-A: A benzyl alcohol derivative represented by formula (Med-1)and a substituent-introducing agent which can be used as a protectinggroup for hydroxyl (for example, a silylating agent or an optionallysubstituted alkylating agent) may be reacted in a solvent or without asolvent and in the presence or in the absence of a base, to afford ahydroxyl-protected derivative represented by formula (Med-2). Thereaction temperature will usually be −70° C. to 200° C. The solvent usedwill differ depending on the starting materials, reagents, etc. and isnot particularly restricted so long as it dissolves the startingmaterials to some degree without inhibiting the reaction, and preferablythere may be mentioned tetrahydrofuran, diethyl ether,N,N-dimethylformamide and dimethylsulfoxide, which may be used alone oras a mixed solvent. As examples of bases to be used there may bementioned sodium hydride, potassium hydride, potassium carbonate, sodiumcarbonate, cesium carbonate, potassium hydroxide, sodium hydroxide,triethylamine, pyridine, imidazole, 2,6-lutidine, and the like. Assilylating agents there may be mentioned trimethylsilyl chloride,tert-butyldimethylsilyl chloride and tert-butyldiphenylsilyl chloride.As substituted alkylating agents there may be mentioned methoxymethylchloride and benzyl chloride. In this case, the substituent-introducingagent may be used at 1 to 3 equivalents and the base at 1 to 5equivalents.

Step 10-B: A compound represented by formula (Med-2) or (Med-3) and analkyllithium reagent (for example, n-butyllithium, sec-butyllithium,tert-butyllithium, etc.) or a Grignard reagent (for example,methylmagnesium bromide, isopropylmagnesium bromide, etc.) may bereacted in an inert solvent and then reacted with a boric acid ester orthe like to afford a boric acid derivative represented by formula (B-1).The reaction temperature will usually be −100° C. to 80° C. The boricacid ester used will differ depending on the starting materials,solvents, etc. and is not particularly restricted so long as it does notinhibit the reaction, and preferably there may be mentioned trimethylborate, triethyl borate, triisopropyl borate,2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborane, and the like. The inertsolvent used will differ depending on the starting materials, reagents,etc. and is not particularly restricted so long as it dissolves thestarting materials to some degree without inhibiting the reaction, andpreferably there may be mentioned hexane, pentane, tetrahydrofuran anddiethyl ether, which may be used alone or as a mixed solvent. When analkyllithium reagent is used, a metal complex-forming agent (forexample, N,N,N′,N′-tetramethylethylenediamine, hexamethylphosphoroustriamide (HMPA), etc.) may also be added to increase the reactivity. Thealkyllithium reagent or Grignard reagent is preferably used at 1 to 2equivalents, the boric acid ester at 1 to 3 equivalents and the metalcomplex-forming agent at 1 to 2 equivalents.

Step 10-C: A compound represented by formula (Med-2) or (Med-3) may besubjected to coupling reaction with alkoxydiboron or pinacolborane in asolvent or without a solvent and in the presence or in the absence of abase, using a transition metal catalyst such as palladium, to affordcompound (B-1). The reaction temperature will usually be 0° C. to 250°C. The inert solvent used will differ depending on the startingmaterials, reagents, etc. and is not particularly restricted so long asit dissolves the starting materials to some degree without inhibitingthe reaction, and preferably there may be mentioned toluene, xylene,1,4-dioxane, dichloroethane, acetonitrile, N,N-dimethylformamide anddimethylsulfoxide, which may be used alone or as a mixed solvent. Thebase used will differ depending on the starting materials, reagents,etc. and is not particularly restricted so long as it does not inhibitthe reaction, and preferably there may be mentioned triethylamine,diisopropylethylamine, pyridine, potassium acetate,1,8-diazabicyclo[5.4.0]-7-undecene (DBU), and the like. Thealkoxydiboron used will differ depending on the starting materials,reagents, etc. and is not particularly restricted so long as it does notinhibit the reaction, and preferably there may be mentioned,bis(pinacolato)diboron, bis(neopentyl glycolato)diboron, bis(hexyleneglycolato)diboron, and the like. The palladium catalyst used will alsodiffer depending on the starting materials, reagents, etc. and is notparticularly restricted so long as it does not inhibit the reaction, andpreferably there may be mentionedtetrakis(triphenylphosphine)palladium(0), palladium(II)acetate/triphenylphosphine, palladium(II) chloride,tris(dibenzylideneacetone)dipalladium(0)/tri-tert-butylphosphine,dichloro[1,1′-bis(diphenylphosphine)-ferrocene]palladium(0),[1,2-bis(diphenylphosphino)ethane]dichloronickel(II),[1,3-bis(diphenylphosphino)propane]dichloronickel(II), and the like. Thetransition metal catalyst is preferably used at 0.001 to 0.2 equivalent,the base at 1 to 20 equivalents and the alkoxyborane or pinacolborane at1 to 3 equivalents.

Step 11-A: A derivative represented by formula (Med-4) and analkyllithium reagent (for example, n-butyllithium, sec-butyllithium,tert-butyllithium, etc.) or Grignard reagent (for example,methylmagnesium bromide, isopropylmagnesium bromide, etc.) may bereacted in an inert solvent, and then reacted with a trialkyltin halidereagent to afford a trialkyltin derivative represented by formula (S-1).The reaction temperature will usually be −100° C. to 50° C. Thetrialkyltin halide reagent used will differ depending on the startingmaterials, solvents, etc. and is not particularly restricted so long asit does not inhibit the reaction, and preferably there may be mentionedtrimethyltin chloride, triethyltin chloride, tributyltin chloride,trimethyltin bromide, triethyltin bromide and tributyltin bromide. Theinert solvent used will differ depending on the starting materials,reagents, etc. and is not particularly restricted so long as itdissolves the starting materials to some degree without inhibiting thereaction, and preferably there may be mentioned hexane, pentane,tetrahydrofuran and diethyl ether, which may be used alone or as a mixedsolvent. When an alkyllithium reagent is used, a metal complex-formingagent (for example, N,N,N′,N′-tetramethylethylenediamine,hexamethylphosphorous triamide (HMPA), etc.) may also be added toincrease the reactivity. The alkyllithium reagent or Grignard reagent ispreferably used at 1 to 2 equivalents, the metal complex-forming agentat 1 to 2 equivalents and the trialkyltin halide at 1 to 2 equivalents.

Step 11-B: A compound represented by formula (Med-4) may be subjected tocoupling reaction with hexamethylditin(IV), bis(tributyltin(IV) or thelike in the same manner as Step C in Production Scheme 10, to afford atrialkyltin derivative represented by formula (S-1).

Step 12-A: A compound represented by formula (20) may be subjected tocoupling reaction with a metal aryl reagent represented by formula (M-2)in the presence of a transition metal catalyst, in the same manner asStep 5-E in Production Scheme 5 above, to afford a derivativerepresented by formula (I^(a1)).

Step 12-B: A pyrazolo[1,5-a]pyridine derivative represented by formula(I^(a1)) having a protected hydroxyl group may be subjected todeprotection reaction suitable for the protecting group to obtain apyrazolo[1,5-a]pyridine derivative represented by formula (I^(a2))having an alcoholic group. The deprotection reaction is carried out atbetween −80° C. to 200° C., in the presence or in the absence of adeprotecting reagent, and in a solvent or without a solvent. Forexample, when the protection is with a silyl group, the solvent usedwill differ depending on the starting materials, reagents, etc. and isnot particularly restricted so long as it dissolves the startingmaterials to some degree without inhibiting the reaction, and preferablythere may be mentioned ethyl acetate, tetrahydrofuran, diethyl ether,dioxane, acetonitrile, methanol, ethanol, dichloromethane, chloroform,nitromethane, phenol, anisole and thiophenol, which may be used alone oras a mixed solvent. As examples of deprotecting reagents to be usedthere may be mentioned fluorine anion-generating compounds such astetrabutylammonium fluoride, hydrogen fluoride and cesium fluoride,acids such as hydrochloric acid, sulfuric acid, trifluoroacetic acid andmethanesulfonic acid, or bases such as potassium carbonate, sodiumcarbonate, sodium hydroxide and potassium hydroxide. In the case of abenzyl ether or the like, the benzyl group may be deprotected byhydrogenation reaction in a solvent such as ethanol, in the presence ofa metal catalyst such as Pd—C.

Step 13-A: A pyrazolo[1,5-a]pyridine derivative represented by formula(I^(a3)) having a primary alcoholic group may be subjected to oxidationreaction in a solvent or without a solvent in the presence of anoxidizing agent, to afford an aldehyde derivative represented by formula(I^(a4)). The reaction temperature will usually be −78° C. to 150° C.The solvent used will differ depending on the starting materials,reagents, etc. and is not particularly restricted so long as itdissolves the starting materials to some degree without inhibiting thereaction, and preferably there may be mentioned tetrahydrofuran, diethylether, 1,2-dichloroethane, dichloromethane, chloroform, acetonitrile,toluene and dimethylsulfoxide, which may be used alone or as a mixedsolvent. As oxidizing agents to be used there may be mentioned oxalylchloride utilized as an activating agent for dimethylsulfoxide oxidation(Swern oxidation), as well as metal reagents such as activated manganesedioxide, sulfur trioxide-pyridine complex, pyridinium chlorochromate(PCC), pyridinium dichromate (PDC),2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and Dess-Martin reagent.The oxidizing agent is preferably used at 1 to 30 equivalents.

Step 13-B: A pyrazolo[1,5-a]pyridine derivative represented by formula(I^(a4)) having an aldehyde group may be reacted with an alkyl metalreagent such as a Grignard reagent, alkyllithium, alkylzinc oralkylcesium, either in an inert solvent or without a solvent, to afforda pyrazolo[1,5-a]pyridine derivative represented by formula (I^(a5)).The reaction temperature will usually be −80° C. to 80° C. The solventused will differ depending on the starting materials, reagents, etc. andis not particularly restricted so long as it dissolves the startingmaterials to some degree without inhibiting the reaction, and preferablythere may be mentioned hexane, pentane, tetrahydrofuran and diethylether, which may be used alone or as a mixed solvent. The alkyl metalreagent is preferably used at 1 to 2 equivalents.

Step 14-A: A pyrazolo[1,5-a]pyridine derivative represented by formula(I^(a3)) having a hydroxyl group may be reacted with an alkylating agent(alkyl halide, dialkylsulfuric acid, alkylsulfonic acid ester, etc.) orthe like, either in a solvent or without a solvent, in the presence orin the absence of a base and in the presence or in the absence of aphase transfer catalyst, to afford a hydroxyl-alkylatedpyrazolo[1,5-a]pyridine derivative represented by formula (I^(a6)). Thereaction temperature will usually be −10° C. to 200° C. The solvent usedwill differ depending on the reagents, etc. and is not particularlyrestricted so long as it dissolves the starting materials to some degreewithout inhibiting the reaction, and preferably there may be mentionedtetrahydrofuran, acetone, N,N-dimethylformamide, dimethylsulfoxide,ethanol, acetonitrile, toluene and water, which may be used alone or asa mixed solvent. The base used will differ depending on the solvent,etc. and is not particularly restricted so long as it does not inhibitthe reaction, and preferably there may be mentioned potassium hydride,sodium hydride, potassium tert-butoxide, potassium carbonate, sodiumcarbonate, calcium carbonate, potassium hydroxide, sodium hydroxide,barium hydroxide, silver oxide, barium oxide, and the like. The phasetransfer catalyst used will differ depending on the solvent, etc. and isnot particularly restricted so long as it does not inhibit the reaction,and preferably there may be mentioned tetrabutylammonium iodide,tetrabutylammonium bromide, and tetrabutylammonium hydrogensulfate. Thealkylating agent is preferably used at 1 to 2 equivalents, the base at 1to 2 equivalents and the phase transfer catalyst at 1 to 2 equivalents.

Step 15-A: The following is a production scheme for apyrazolo[1,5-a]pyridine derivative represented by formula (I^(a7)),wherein the hydroxyl group of a pyrazolo[1,5-a]pyridine derivativerepresented by formula (I^(a3)) having a hydroxyl group is converted toa leaving group.

Sulfonic acid esterification reaction: A pyrazolo[1,5-a]pyridinederivative represented by formula (I^(a3)) having a hydroxyl group maybe reacted with a sulfonic acid esterification reagent at 0° C. to 250°C., either in a solvent or without a solvent and in the presence or inthe absence of a base, to afford a sulfonic acid ester derivativerepresented by formula (I^(a7)). The sulfonic acid esterificationreagent used will differ depending on the solvent, etc. and is notparticularly restricted so long as it does not inhibit the reaction, andpreferably there may be mentioned methanesulfonyl chloride, tosylchloride, tosyl fluoride, methanesulfonic anhydride, tosylic anhydride,trifluoromethanesulfonic anhydride, and the like. The base used willdiffer depending on the solvent, etc. and is not particularly restrictedso long as it does not inhibit the reaction, and preferably there may bementioned triethylamine, N-methylmorpholine, pyridine and the like. Thesolvent used will differ depending on the reagents, etc. and is notparticularly restricted so long as it dissolves the starting materialsto some degree without inhibiting the reaction, and preferably there maybe mentioned dichloromethane, diethyl ether, tetrahydrofuran, tert-butylether, acetonitrile, N,N-dimethylformamide, dimethylsulfoxide andtoluene, which may be used alone or as a mixed solvent. The sulfonicacid esterification reagent is preferably used at 1 to 2 equivalents andthe base at 1 to 2 equivalents.

Halogenation (chlorination, bromination, iodination) reaction: Apyrazolo[1,5-a]pyridine derivative represented by formula (I^(a3))having a hydroxyl group may be reacted with a halogenating agent such asN-chlorosuccinimide, phosphorous oxychloride, thionyl chloride, carbontetrabromide, N-bromosuccinimide, bromine, phosphorus tribromide,phosphorus pentabromide, iodine or the like or with triphenylphosphineand carbon tetrachloride or carbon tetrabromide, at 0° C. to 250° C.either in a solvent or without a solvent, to afford a halogenatedcompound (I^(a7)). A base such as triethylamine, imidazole or4-(dimethylamino)pyridine may also be added to the reaction mixture. Thesolvent used will differ depending on the reagents, etc. and is notparticularly restricted so long as it dissolves the starting materialsto some degree without inhibiting the reaction, and preferably there maybe mentioned dichloromethane, toluene and N,N-dimethylformamide, whichmay be used alone or as a mixed solvent. Compound (I^(a7)) may also beobtained by direct reaction of a compound represented by formula(I^(a3)) with thionyl chloride, methanesulfonyl chloride or the like at0° C. to 250° C. either in a solvent or without a solvent.

Fluorination reaction: A pyrazolo[1,5-a]pyridine derivative representedby formula (I^(a3)) having a hydroxyl group may be reacted with afluorinating reagent at −78° C. to 0° C., either in a solvent or withouta solvent, to afford a fluorinated pyrazolo[1,5-a]pyridine derivativerepresented by formula (I^(a7)). The solvent used will differ dependingon the reagents and is not particularly restricted so long as itdissolves the starting materials to some degree without inhibiting thereaction, and preferably there may be mentioned dichloromethane,diglyme, isooctane and monofluorotrichloromethane, which may be usedalone or as a mixed solvent. The fluorinating reagent used will differdepending on the solvent, etc. and is not particularly restricted solong as it does not inhibit the reaction, and preferably there may bementioned diethylaminosulfur trifluoride (DAST), sulfur tetrafluoride,morpholinosulfur trifluoride (morph-DAST), and the like. Thefluorinating reagent is preferably used at 1 to 5 equivalents.

Step 15-B: A pyrazolo[1,5-a]pyridine derivative represented by formula(I^(a7)) may be reacted with a nucleophilic reagent such as an alkalimetal salt of an alkoxide at −78° C. to 250° C., either in a solvent orwithout a solvent, to afford a pyrazolo[1,5-a]pyridine derivativerepresented by formula (I^(a6)). The solvent used will differ dependingon the starting materials, reagents, etc. and is not particularlyrestricted so long as it dissolves the starting materials to some degreewithout inhibiting the reaction, and preferably there may be mentionedtetrahydrofuran, diethyl ether, N,N-dimethylformamide,dimethylsulfoxide, toluene and ethanol, which may be used alone or as amixed solvent. As nucleophilic reagents there may be mentioned alkalimetal salts of alkoxides, and specifically there may be mentioned sodiummethoxide, sodium ethoxide, and the like. The nucleophilic reagent ispreferably used at 1 to 2 equivalents.

Step 15-C: A pyrazolo[1,5-a]pyridine derivative represented by formula(I^(a7)) having a leaving group may be reacted with a nucleophilicreagent at −78° C. to 250° C., either in a solvent or without a solvent,to afford a pyrazolo[1,5-a]pyridine derivative represented by formula(I^(a8)). The solvent used will differ depending on the startingmaterials, reagents, etc. and is not particularly restricted so long asit dissolves the starting materials to some degree without inhibitingthe reaction, and preferably there may be mentioned tetrahydrofuran,diethyl ether, N,N-dimethylformamide, dimethylsulfoxide, toluene andethanol, which may be used alone or as a mixed solvent. As nucleophilicreagents there may be mentioned amines such as ammonia, methylamine,dimethylamine, morpholine and piperidine, or alkali metal salts ofthioalkoxides. The nucleophilic reagent is preferably used at 1 to 2equivalents.

Alternatively, compound (I^(a8)) having an amino group may be obtainedby reaction with sodium azide, sodium di-tert-butyliminodicarboxylate,sodium phthalimide or the like as a nucleophilic reagent, followed byreduction and deprotection reactions, etc.

In addition, compound (I^(a8)) having a thiol group may be obtained byreaction with potassium thioacetate, thiourea or the like as anucleophilic reagent, followed by appropriate reactions.

Step 15-D: A pyrazolo[1,5-a]pyridine derivative represented by formula(I^(a3)) having a hydroxyl group may be converted to apyrazolo[1,5-a]pyridine derivative represented by formula (I^(a8)) byMitsunobu reaction using a diazo compound such as diethylazodicarboxylate and an aminating reagent or the like in the presence ofan organic phosphorus compound, in a solvent or without a solvent. Thereaction temperature will usually be −70° C. to 80° C. As examples ofaminating reagents there may be mentioned phthalimides and the like. Asexamples of phosphine compounds there may be mentionedtriphenylphosphine, tributylphosphine and the like, and as examples ofazodicarboxylate compounds there may be mentioned diethylazodicarboxylate, diisopropyl azodicarboxylate, and the like. Thesolvent used will differ depending on the starting materials, reagents,etc. and is not particularly restricted so long as it dissolves thestarting materials to some degree without inhibiting the reaction, andpreferably there may be mentioned tetrahydrofuran, diethyl ether andtoluene, which may be used alone or as a mixed solvent.

Step 16-A: A pyrazolo[1,5-a]pyridine derivative represented by formula(I^(a4)) having an aldehyde group may be reacted in the same manner asSteps 5-C and 5-D in Production Scheme 5 above to afford apyrazolo[1,5-a]pyridine derivative (I^(a9)) having an optionallysubstituted amino group.

Representative production schemes for compound (I) according to thepresent invention have been described above, but the starting compoundsand reagents used for production of the compounds of the invention mayalso form salts or hydrates which will differ depending on the startingmaterials and solvents used, and these are not particularly restrictedso long as the reaction is not inhibited. The solvents used will alsodiffer depending on the starting materials and reagents, and they arenot particularly restricted so long as they do not inhibit the reactionand dissolve the starting materials to some degree. When compound (I) ofthe present invention is obtained as a free compound, a common methodmay be used to convert it to a salt which compound (I) can form. Thedifferent isomers (for example, geometric isomers, optical isomers basedon asymmetric carbon, rotational isomers, stereoisomers and tautomers)obtained for compound (I) according to the invention may be purified andisolated using common separation means such as recrystallization,diastereomer salt methods, enzymatic separation methods andchromatography methods (for example, thin-layer chromatography, columnchromatography, gas chromatography, etc.).

Compounds represented by formula (I) according to the present inventionand salts thereof or hydrates of the foregoing may be used directly orin admixture with publicly known pharmaceutically acceptable carriers,and formulated by common methods. As preferred dosage forms there may bementioned tablets, powders, fine particles, granules, coated tablets,capsules, syrups, lozenges, inhalants, suppositories, injections,ointments, eye salves, eye drops, nasal drops, ear drops, paps, lotionsand the like. For the formulation there may be employed any commonlyused excipients, binders, disintegrators, lubricants, coloring agents,corrective coatings, and if necessary, stabilizers, emulsifiers,absorbefacients, surfactants, pH adjustors, preservatives, antioxidants,or the like, in combination with various components that are ordinarilyused as starting materials for pharmaceutical formulations.

As such components there may be mentioned animal and vegetable oils suchas soybean oil, beef tallow and synthetic glycerides; hydrocarbons suchas liquid paraffin, squalane and solid paraffin; ester oils such asoctyldodecyl myristate and isopropyl myristate; higher alcohols such ascetostearyl alcohol and behenyl alcohol; silicone resins; silicone oils;surfactants such as polyoxyethylene fatty acid esters, sorbitan fattyacid esters, glycerin fatty acid esters, polyoxyethylene sorbitan fattyacid esters, polyoxyethylene hydrogenated castor oil andpolyoxyethylene-polyoxypropylene block copolymer; water-soluble polymerssuch as hydroxyethylcellulose, polyacrylic acid, carboxyvinyl polymer,polyethylene glycol, polyvinylpyrrolidone and methylcellulose; loweralcohols such as ethanol and isopropanol; polyhydric alcohols such asglycerin, propylene glycol, dipropylene glycol and sorbitol; sugars suchas glucose and sucrose; inorganic powders such as silicic anhydride,magnesium aluminum silicate and aluminum silicate; purified water, andthe like. Examples of excipients which may be used include lactose, cornstarch, white soft sugar, glucose, mannitol, sorbit, crystallinecellulose and silicon dioxide; examples of binders which may be usedinclude polyvinyl alcohol, polyvinyl ether, methylcellulose,ethylcellulose, gum arabic, tragacanth, gelatin, shellac,hydroxypropylcellulose, hydroxypropylmethyl cellulose,polyvinylpyrrolidone, polypropylene glycol/polyoxyethylene block polymerand meglumine, calcium citrate, dextrin pectin andcarboxymethylcellulose calcium; examples of disintegrators which may beused include starch, agar, gelatin powder, crystalline cellulose,calcium carbonate, sodium hydrogencarbonate, calcium citrate, dextrin,pectin and carboxymethylcellulose calcium; examples of lubricants whichmay be used include magnesium stearate, talc, polyethylene glycol,silica and hydrogenated vegetable oils; examples of coloring agentswhich may be used include any of those approved for addition to drugs;examples of corrective coatings which may be used include cocoa powder,menthol, aromatic powders, mentha oil, borneol and powdered cinnamon;and examples of antioxidants which may be used include those approvedfor addition to drugs, such as ascorbic acid and alpha-tocopherol.

An oral formulation may be prepared by combining a compound of thepresent invention or salt thereof with an excipient, if necessary addinga binder, disintegrator, lubricant, coloring agent, corrective coatingor the like, and forming a powder, fine particles, granules, tablets,coated tablets, capsules, etc. by a common method.

The tablets or granules may, of course, also be coated with a sugarcoating, gelatin coating or other type of suitable coating if necessary.

In the case of a liquid formulation such as syrup, injection, eye dropsor the like, a common method may be used for formulation with a pHadjustor, solubilizer, isotonizing agent or the like, as well as asolubilizing aid, stabilizer, buffering agent, suspending agent,antioxidant, etc. if necessary. In the case of a liquid formulation, itmay also be lyophilized, and an injection may be administeredintravenously, subcutaneously or intramuscularly. As preferred examplesof suspending agents there may be mentioned methyl cellulose,polysorbate 80, hydroxyethyl cellulose, gum arabic, tragacanth powder,sodium carboxymethylcellulose, polyoxyethylene sorbitan monolaurate andthe like; as preferred examples of solubilizing aids there may bementioned polyoxyethylene hydrogenated castor oil, polysorbate 80,nicotinamide, polyoxyethylene sorbitan monolaurate and the like; aspreferred examples of stabilizing agents there may be mentioned sodiumsulfite, sodium metasulfite, ether and the like; and as preferredexamples of preservatives there may be mentioned methyl paraoxybenzoate,ethyl paraoxybenzoate, sorbic acid, phenol, cresol, chlorocresol, andthe like.

There are no particular restrictions on the method of preparing anexternal agent, and any common method may be employed. The basematerials used may be any raw materials commonly employed in drugs,quasi drugs, cosmetics and the like, and as examples there may bementioned raw materials such as animal and vegetable oils, mineral oils,ester oils, waxes, higher alcohols, fatty acids, silicone oils,surfactants, phospholipids, alcohols, polyhydric alcohols, water-solublepolymers, clay minerals, purified water and the like, with addition ofpH adjustors, antioxidants, chelating agents, antiseptics andfungicides, coloring agents, aromas and the like if necessary. Also, ifnecessary, there may also be included differentiation-inducingcomponents, or other components such as circulation promoters,microbicides, antiphlogistic agents, cell activators, vitamins, aminoacids, humectants, keratolytic agents and the like.

Drug formulations comprising compound (I) of the present invention andsalt thereof or hydrate of the foregoing as effective ingredients areuseful for disease treatment or prevention in mammals (for example,humans, mice, rats, guinea pigs, rabbits, dogs, horses, monkeys, etc.),and especially for disease treatment or prevention in humans. Althoughthe dosage of a drug according to the present invention will differdepending on the patient's severity of symptoms, age, gender, bodyweight, the dosage form, type of salt, drug sensitivity and specifictype of disease, etc., it will generally be from about 30 μg to 10 g,preferably from 100 μg to 500 mg, more preferably from 100 μg to 100 mgper day for adult humans in the case of oral administration or about1-3000 μg/kg and preferably 3-1000 μg/kg in the case of injection,administered once or divided over several times a day.

EXAMPLES

The following production examples, examples and test examples serve onlyfor the purpose of illustration and are not intended to be restrictiveon the compounds of the invention in any way. It will be apparent tothose skilled in the art that various modifications may be added beyondthese examples and within the scope of the claims of the invention inthe present specification in order to maximize the effect of theinvention, and such modifications are also encompassed within theclaims.

The phrase “purified by silica gel column chromatography and the titlecompound was obtained from . . . fraction” in the present specificationmeans to obtain the title compound by concentrating the solution of thefractions containing the target compound obtained by silica gel columnchromatography, and, if necessary, further by recrystallization.

Production Example 1 2-(1-Butynyl)pyridine

To a solution of 2-bromopyridine (50 g) dissolved in diethylamine (500mL) was added dichlorobis(triphenylphosphine)palladium(II) (2.2 g) andcopper iodide (0.3 g), and the reaction mixture was stirred for 4 hoursat room temperature while introducing 1-butyne (100 g) as a gas. Theresulting reaction mixture was bubbled with nitrogen, and then ethylacetate was added. After the reaction mixture was filtered throughcelite to remove insoluble residue, the filtrate was washed with waterand brine. The obtained organic extract was dried over anhydrousmagnesium sulfate and filtered, the solvent was evaporated under reducedpressure, the residue was purified by silica gel column chromatographyand the title compound (35 g) was obtained as a brown oil from then-hexane:ethyl acetate (5:1) fraction.

¹H NMR (400 MHz, CDCl₃) δ 1.26 (t, J=7.6 Hz, 3H), 2.45 (q, J=7.6 Hz,2H), 7.16-7.20 (m, 1H), 7.35-7.38 (m, 1H), 7.59-7.63 (m, 1H), 8.53-8.54(m, 1H).

Production Example 2 2-Ethylpyrazolo[1,5-a]pyridine

To a solution of 2-(1-butynyl)pyridine (12.8 g) dissolved indichloromethane (60 mL) was added a solution ofO-mesitylenesulfonylhydroxylamine (Reference; Synthesis, 1997, 1) (20 g)in dichloromethane (132 mL) while cooling with ice, and the reactionmixture was stirred for 30 minutes. Diethyl ether (2 L) was added to thereaction mixture to precipitate crystals, which were filtered off andthen dried under reduced pressure to afford a crude product ofN-amino-2-(1-butynyl)pyridinium mesitylenesulfonate (12.6 g) ascolorless crystals.

A portion (6.1 g) of the obtained crude product ofN-amino-2-(1-butynyl)pyridinium mesitylenesulfonate was dissolved intetrahydrofuran (600 mL), and then potassium tert-butoxide (3.55 g) wasadded thereto at room temperature and the reaction mixture wasvigorously stirred for 30 minutes. After adding ice water to theobtained reaction mixture, extraction was performed with ethyl acetate.After re-extraction of the aqueous layer with ethyl acetate and theinsoluble residue was filtered with celite, the organic extracts werecombined and washed with brine. The obtained organic extract was driedover anhydrous magnesium sulfate and filtered, the solvent wasevaporated under reduced pressure, the residue was purified by silicagel column chromatography and the title compound (0.63 g) was obtainedas a light yellow oil from the n-hexane:ethyl acetate (10:1) fraction.

¹H NMR (400 MHz, CDCl₃) δ 1.36 (t, J=7.6 Hz, 3H), 2.86 (q, J=7.6 Hz,2H), 6.30 (s, 1H), 6.65 (ddd, J=1.6, 6.8, 6.8 Hz, 1H), 7.04 (ddd, J=1.2,6.8, 8.8 Hz, 1H), 7.41 (ddd, J=1.2, 1.2, 8.8 Hz, 1H), 8.37 (ddd, J=1.2,1.2, 6.8 Hz, 1H).

Production Example 3 7-Bromo-2-ethylpyrazolo[1,5-a]pyridine

To a solution of 2-ethylpyrazolo[1,5-a]pyridine (80 mg) dissolved intetrahydrofuran (1 mL) was added n-butyllithium (1.6M hexane solution:0.58 mL) dropwise at −78° C. under a nitrogen stream, and the reactionmixture was further stirred for 30 minutes at the same temperature. Asolution of 1,2-dibromo-1,1,2,2-tetrachloroethane (196 mg) intetrahydrofuran (0.5 mL) was added dropwise to the reaction mixture, andstirring was continued for 30 minutes. After raising the temperature toroom temperature and adding water to the reaction mixture, extractionwas performed with ethyl acetate and the organic extract was washed withwater and brine. The obtained organic extract was dried over anhydrousmagnesium sulfate and filtered, the solvent was evaporated under reducedpressure, the residue was purified by silica gel column chromatographyand the title compound (90 mg) was obtained as a light brown oil fromthe n-hexane:ethyl acetate (20:1) fraction.

¹H NMR (400 MHz, CDCl₃) δ 1.36 (t, J=7.6 Hz, 3H), 2.93 (q, J=7.6 Hz,2H), 6.49 (s, 1H), 6.94 (dd, J=7.2, 8.4 Hz, 1H), 6.99 (dd, J=1.6, 7.2Hz, 1H), 7.44 (dd, J=1.6, 8.4 Hz, 1H).

Production Example 4 7-Bromo-2-ethyl-3-nitropyrazolo[1,5-a]pyridine

To a solution of 7-bromo-2-ethylpyrazolo[1,5-a]pyridine (1.1 g)dissolved in acetonitrile (20 mL) was added nitronium tetrafluoroborate(1.3 g) was added thereto while cooling with ice, and the reactionmixture was stirred for 30 minutes. The reaction mixture was then addedto ice water, extraction was performed with ethyl acetate, and theorganic extract was washed with water and brine. The obtained organicextract was dried over anhydrous magnesium sulfate and filtered, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography and the title compound (670mg) was obtained as yellow crystals from the n-hexane:ethyl acetate(10:1) fraction.

¹H NMR (400 MHz, CDCl₃) δ 1.42 (t, J=7.6 Hz, 3H), 3.27 (q, J=7.6 Hz,2H), 7.39 (dd, J=1.2, 7.6 Hz, 1H), 7.50 (dd, J=7.6, 8.8 Hz, 1H), 8.38(dd, J=1.2, 8.8 Hz, 1H).

Production Example 5 7-Bromo-2-ethylpyrazolo[1,5-a]pyridine-3-amine

To a suspension of 7-bromo-2-ethyl-3-nitropyrazolo[1,5-a]pyridine (1.78g) in a mixed solution of ethanol (100 mL), water (50 mL) and aceticacid (10 mL) was added zinc powder (1.78 g) at room temperature and thereaction mixture was stirred for 1 hour at 65° C. The reaction mixturewas filtered through celite to remove insoluble residue and the filtratewas evaporated under reduced pressure. Water was added to the obtainedresidue and extraction was performed with ethyl acetate, and afterwashing the organic extract with water, saturated aqueous sodiumbicarbonate and brine, the organic extract was dried over anhydrousmagnesium sulfate and filtered, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (60 g) and the title compound (1.16 g) was obtained as adark green oil from the ethyl acetate:n-hexane (4:1) fraction.

¹H NMR (400 MHz, CDCl₃) δ 1.36 (t, J=7.6 Hz, 3H), 2.89 (q, J=7.6 Hz,2H), 6.81 (dd, J=7.1, 8.7 Hz, 1H), 6.88 (dd, J=1.3, 7.0 Hz, 1H), 7.34(dd, J=1.3, 8.6 Hz, 1H).

Production Example 6 tert-ButylN-(7-bromo-2-ethylpyrazolo[1,5-a]pyridin-3-yl)carbamate

To a solution of 7-bromo-2-ethylpyrazolo[1,5-a]pyridine-3-amine (1.16 g)in dichloromethane (50 mL) was added triethylamine (1.01 mL) anddi-tert-butyl dicarbonate (1.34 mL) at room temperature, and thereaction mixture was stirred for 15 hours. After completion of thereaction, the solvent was evaporated under reduced pressure. Ethylacetate was added to the residue, and the obtained organic extract waswashed with water and brine, and dried over anhydrous magnesium sulfateand filtered, then the solvent was evaporated under reduced pressure.The obtained residue was purified by silica gel column chromatography(60 g) and the title compound (1.09 g) was obtained as hazel crystalsfrom the ethyl acetate:n-hexane (1:3) fraction.

¹H NMR (400 MHz, CDCl₃) δ 1.34 (t, J=7.6 Hz, 3H), 1.52 (br s, 9H), 2.87(q, J=7.6 Hz, 2H), 5.91 (br s, 1H), 6.92-7.04 (m, 2H), 7.40 (d, J=9.0Hz, 1H).

Production Example 7N-(7-Bromo-2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-cyclopropylmethylamine

To a solution of tert-butylN-(7-bromo-2-ethylpyrazolo[1,5-a]pyridin-3-yl)carbamate (658 mg) inN,N-dimethylformamide (15 mL) was added sodium hydride (60% in oil; 116mg) at room temperature under a nitrogen stream, and the reactionmixture was stirred for 30 minutes. (Bromomethyl)cyclopropane (0.286 mL)was added thereto at the same temperature, and the reaction mixture wasstirred for 1 hour at 60° C. After completion of the reaction, thereaction mixture was gradually added to ice, ethyl acetate was added andthe organic extract was washed with water and brine, after which it wasdried over anhydrous magnesium sulfate and the solvent was evaporatedunder reduced pressure to afford a crude product of tert-butylN-(7-bromo-2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-cyclopropylmethylcarbamate.

To a solution of crude tert-butylN-(7-bromo-2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-cyclopropylmethylcarbamatedissolved in ethyl acetate (10 mL) was added 4N hydrochloric acid/ethylacetate (30 mL), and the reaction mixture was stirred for 2 hours atroom temperature. After completion of the reaction, a 5N aqueous sodiumhydroxide solution was added to the reaction mixture while cooling withice for neutralization. The reaction mixture was extracted with ethylacetate, and after washing the organic extract with water and brine, itwas dried over anhydrous magnesium sulfate and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (20 g) and the title compound (479 mg) wasobtained as a yellow oil from the ethyl acetate:n-hexane (1:3) fraction.

¹H NMR (400 MHz, CDCl₃) δ 0.14-0.22 (m, 2H), 0.47-0.56 (m, 2H),0.96-1.10 (m, 1H), 1.37 (t, J=7.6 Hz, 3H), 2.88 (d, J=6.8 Hz, 2H), 2.90(q, J=7.6 Hz, 2H), 6.83 (dd, J=7.0, 8.8 Hz, 1H), 6.90 (dd, J=1.3, 7.1Hz, 1H), 7.43 (dd, J=1.3, 8.8 Hz, 1H).

Production Example 8N-(7-Bromo-2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-cyclopropylmethyl-N-tetrahydro-2H-4-pyranylmethylamine

To a solution ofN-(7-bromo-2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-cyclopropylmethylamine(106 mg) in tetrahydrofuran (3 mL) was addedtetrahydropyran-4-carbaldehyde (123 mg) at room temperature, and thensodium triacetoxyborohydride (229 mg) was gradually added. Afterstirring the reaction mixture for 1 hour, saturated aqueous sodiumbicarbonate was added thereto. The obtained mixture was extracted withethyl acetate, and organic extract was washed with brine and then driedover anhydrous magnesium sulfate, and evaporated under reduced pressure.The residue was purified by silica gel column chromatography (10 g) andthe title compound (120 mg) was obtained as a yellow oil from the ethylacetate:n-hexane (1:6) fraction.

¹H NMR (400 MHz, CDCl₃) δ −0.02-0.06 (m, 2H), 0.33-0.43 (m, 2H),0.75-0.88 (m, 1H), 1.20-1.34 (m, 2H), 1.38 (t, J=7.6 Hz, 3H), 1.48-1.62(m, 1H), 1.69-1.78 (m, 2H), 2.88 (d, J=6.8 Hz, 2H), 2.91 (q, J=7.6 Hz,2H), 3.04 (d, J=7.0 Hz, 2H), 3.30 (dt, J=2.1, 12.0 Hz, 2H), 3.90-4.00(m, 2H), 6.88 (dd, J=7.1, 8.8 Hz, 1H), 6.96 (dd, J=1.3, 7.1 Hz, 1H),7.49 (dd, J=1.3, 8.8 Hz, 1H).

Similarly to Production Example 7 and 8, the compound of ProductionExample 9 was obtained.

Production Example 9N-(7-Bromo-2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-butyl-N-tetrahydro-2H-4-pyranylmethylamine

Production Example 107-[2,6-Dimethoxy-4-(methoxymethyl)phenyl]-2-ethyl-3-nitropyrazolo[1,5-a]pyridine

To a solution of 7-bromo-2-ethyl-3-nitropyrazolo[1,5-a]pyridine (1.0 g)dissolved in a mixture of 1,2-dimethoxyethane (50 mL) and water (25 mL)was added 2,6-dimethoxy-4-(methoxymethyl)phenylboric acid (1.26 g),tetrakis(triphenylphosphine)palladium(0) (0.64 g) and barium hydroxideoctahydrate (1.75 g), and the reaction mixture was heated and stirredfor 2 hours at 80° C. To the resultant reaction mixture was added waterand ethyl acetate, and remove insoluble residue was filtered out withcelite. The filtrate was extracted with ethyl acetate, the organicextract was washed with brine, dried over anhydrous magnesium sulfateand filtered, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography andthe title compound (0.77 g) was obtained as yellow crystals from then-hexane:ethyl acetate (3:1) fraction.

¹H NMR (400 MHz, CDCl₃) δ 1.28 (t, J=7.2 Hz, 3H), 3.12 (q, J=7.2 Hz,2H), 3.49 (s, 3H), 3.71 (s, 6H), 4.53 (s, 2H), 6.67 (s, 2H), 7.03 (dd,J=1.6, 7.2 Hz, 1H), 7.65 (dd, J=7.2, 8.8 Hz, 1H), 8.34 (dd, J=1.2, 8.8Hz, 1H).

Production Example 11 7-Bromo-2-methylpyrazolo[1,5-a]pyridine

To a solution of 2-methylpyrazolo[1,5-a]pyridine (Reference; Chem.Pharm. Bull., 1983, 31, 4568-5572) (1.0 g) dissolved in tetrahydrofuran(20 mL) was added n-butyllithium (2.66 M hexane solution; 3.7 mL)dropwise at −78° C. under a nitrogen stream, and the reaction mixturewas stirred for 30 minutes. To the reaction mixture was added a solutionof 1,2-dibromo-1,1,2,2-tetrachloroethane (2.7 g) in tetrahydrofuran (5mL) dropwise, and stirring was continued for 30 minutes. After addingsaturated aqueous ammonium chloride to the obtained reaction mixture,the temperature was raised to room temperature, water was added to thereaction mixture and extraction was performed with ethyl acetate. Theorganic extract was separated, then washed with brine, dried overanhydrous magnesium sulfate and filtered. The solvent was evaporatedunder reduced pressure, the residue was purified by silica gel columnchromatography and the title compound (1.34 g) was obtained as a yellowoil from the n-hexane:ethyl acetate (10:1) fraction.

¹H NMR (400 MHz, CDCl₃) δ 2.55 (s, 3H), 6.45 (s, 1H), 6.93 (dd, J=7.2,8.4 Hz, 1H), 6.97 (dd, J=1.6, 7.2 Hz, 1H), 7.41 (dd, J=1.6, 8.4 Hz, 1H).

Production Example 12 7-Bromo-2-methyl-3-nitropyrazolo[1,5-a]pyridine

To a solution of 7-bromo-2-methylpyrazolo[1,5-a]pyridine (1.3 g)dissolved in acetonitrile (25 mL) was added nitronium tetrafluoroborate(900 mg) while stirring on ice, and the reaction mixture was stirred for10 minutes. The obtained reaction mixture was added to ice water, andthe precipitated crystals were collected by filtration, washed withwater and then dried under reduced pressure to afford crude crystals.These were purified by silica gel column chromatography and the titlecompound (900 mg) was obtained as yellow crystals from then-hexane:ethyl acetate (5:1) fraction.

¹H NMR (400 MHz, CDCl₃) δ 2.85 (s, 3H), 7.38 (dd, J=1.2, 7.6 Hz, 1H),7.49 (dd, J=7.6, 8.8 Hz, 1H), 7.35 (dd, J=1.2, 8.8 Hz, 1H).

Production Example 13 tert-ButylN-(7-bromo-2-methylpyrazolo[1,5-a]pyridin-3-yl)carbamate

To a Suspension of 7-bromo-2-methyl-3-nitropyrazolo[1,5-a]pyridine (890mg) in a mixed solution of ethanol (20 mL), water (10 mL) and aceticacid (2 mL) was added zinc powder (890 mg) at room temperature, and thereaction mixture was heated and stirred for 30 minutes at 60° C. Afterfiltering off the insoluble residue, the filtrate was extracted withethyl acetate and the organic extract was washed with saturated aqueoussodium bicarbonate and brine. The obtained organic extract was driedover anhydrous magnesium sulfate and filtered, the solvent wasevaporated under reduced pressure, the residue was purified by silicagel column chromatography and[7-bromo-2-methylpyrazolo[1,5-a]pyridin-3-yl]amine (371 mg) was obtainedas an brown oil from the n-hexane:ethyl:acetate (1:1) fraction.

To a solution of the obtained[7-bromo-2-methylpyrazolo[1,5-a]pyridin-3-yl]amine and triethylamine(0.342 mL) dissolved in dichloromethane was added di-tert-butyldicarbonate (429 mg) while cooling with ice, and the reaction mixturewas stirred for 15 hours at room temperature. Water was added to theobtained reaction mixture, extraction was performed with ethyl acetate,and the organic extract was washed with water and brine. The obtainedorganic extract was dried over anhydrous magnesium sulfate and filtered,the solvent was evaporated under reduced pressure, the residue waspurified by silica gel column chromatography and the title compound (420mg) was obtained as an ecru oil from the n-hexane:ethyl acetate (5:1)fraction.

¹H NMR (400 MHz, CDCl₃) δ 1.52 (br s, 9H), 2.47 (s, 3H), 5.88-5.92 (m,1H), 6.94-7.00 (m, 2H), 7.37-7.42 (m, 1H).

Similarly to Production Example 7 and 8, the compound of ProductionExample 14 was obtained.

Production Example 14N-(7-Bromo-2-methylpyrazolo[1,5-a]pyridin-3-yl)-N-cyclopropylmethyl-N-tetrahydro-2H-4-pyranylmethylamine

Yellow oil

¹H NMR (400 MHz, CDCl₃) δ −0.04-0.08 (m, 2H), 0.32-0.43 (m, 2H),0.74-0.88 (m, 1H), 1.20-1.36 (m, 2H), 1.46-1.62 (m, 1H), 1.66-1.78 (m,2H), 2.52 (s, 3H), 2.87 (d, J=6.8 Hz, 2H), 3.03 (d, J=6.8 Hz, 2H), 3.30(dt, J=2.0, 12.0 Hz, 2H), 3.89-3.99 (m, 2H), 6.88 (dd, J=1.4, 6.8 Hz,1H), 6.95 (dd, J=6.8, 8.8 Hz, 1H), 7.47 (dd, J=1.4, 8.8 Hz, 1H).

Production Example 15 2-(3-Methoxy-1-propynyl)pyridine

To a solution of 2-bromopyridine (20 g) dissolved in diethylamine (100mL) was added 3-methoxy-1-propyne (11.8 g),dichlorobis(triphenylphosphine)palladium(II) (888 mg) and copper iodide(121 mg), and the reaction mixture was stirred for 1 hour at 40° C.under a nitrogen stream. After the reaction mixture was filtered throughcelite to remove insoluble residue, the filtrate was evaporated underreduced pressure, the residue was purified by silica gel columnchromatography and the title compound (16.8 g) was obtained as a lightorange oil from the n-hexane:ethyl:acetate (5:1) fraction.

¹H NMR (400 MHz, CDCl₃) δ 3.48 (s, 3H), 4.36 (s, 2H), 7.22-7.26 (m, 1H),7.44-7.47 (m, 1H), 7.66 (ddd, J=1.6, 7.6, 7.6 Hz, 1H), 8.57-8.60 (m,1H).

Production Example 16 2-(Methoxymethyl)pyrazolo[1,5-a]pyridine

To a solution of 2-(3-methoxy-1-propynyl)pyridine (13.2 g) dissolved indichloromethane (50 mL) was added a solution ofO-mesitylenesulfonylhydroxylamine (Reference; Synthesis, 1997, 1) (21 g)in dichloromethane (80 mL) dropwise while cooling with ice, and thereaction mixture was stirred for 30 minutes. Diethyl ether (1 L) wasadded to the obtained reaction mixture to precipitate crystals, whichwere collected by filtration and dried under reduced pressure to afforda crude product of 1-amino-2-(3-methoxy-1-propynyl)pyridinium2,4,6-trimethyl-1-benzenesulfonate as ecru crystals (27.1 g).

To a solution of the obtained crude product of1-amino-2-(3-methoxy-1-propynyl)pyridinium2,4,6-trimethyl-1-benzenesulfonate (27.1 g) dissolved in methanol (100mL) was added sodium methoxide (28% methanol solution; 14.3 mL) dropwisewhile cooling with ice, and the reaction mixture was stirred for 20minutes at room temperature. After adding ice water to the obtainedreaction mixture, the methanol was evaporated under reduced pressure,water was added to the residue and extraction was performed 3 times withethyl acetate. The organic extracts were combined, washed with brine,dried over anhydrous magnesium sulfate and filtered, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography and the title compound (3.54 g) was obtainedas a light orange oil from the n-hexane:ethyl acetate (5:1) fraction.

¹H NMR (400 MHz, CDCl₃) δ 3.47 (s, 3H), 4.68 (s, 2H), 6.50 (s, 1H),6.70-6.75 (m, 1H), 7.06-7.11 (m, 1H), 7.47-7.50 (m, 1H), 8.40-8.43 (m,1H).

Production Example 17 (7-Bromopyrazolo[1,5-a]pyridin-2-yl)methyl methylether

To a solution of 2-(methoxymethyl)pyrazolo[1,5-a]pyridine (3.5 g)dissolved in tetrahydrofuran (350 mL) was added n-butyllithium (2.66Mhexane solution; 10.5 mL) dropwise at −78° C. under a nitrogen stream,and the reaction mixture was stirred for 30 minutes. 1,2-Dibromoethane(2.05 mL) was added dropwise to the obtained reaction mixture andstirring was continued for 30 minutes. After adding saturated aqueousammonium chloride to the reaction mixture, the temperature was raised toroom temperature, water was added and extraction was performed withethyl acetate. The organic extract was washed with brine, dried overanhydrous magnesium sulfate and filtered. The solvent was evaporatedunder reduced pressure, the residue was purified by silica gel columnchromatography and the title compound (2.75 g) was obtained as a lightyellow oil from the n-hexane:ethyl acetate (10:1) fraction.

¹H NMR (400 MHz, CDCl₃) δ 3.47 (s, 3H), 4.75 (s, 2H), 6.71 (s, 1H), 6.99(dd, J=7.2, 8.8 Hz, 1H), 7.05 (dd, J=1.2, 7.2 Hz, 1H), 7.51 (dd, J=1.2,8.8 Hz, 1H).

Production Example 18 (7-Bromo-3-nitropyrazolo[1,5-a]pyridin-2-yl)methylmethyl ether

To a solution of (7-bromopyrazolo[1,5-a]pyridin-2-yl)methyl methyl ether(1.0 g) dissolved in acetonitrile (20 mL) was added nitroniumtetrafluoroborate (606 mg) while stirring on ice. The obtained reactionmixture was added to ice water, extracted with ethyl acetate and thenwashed with water and brine. The obtained organic extract was dried overanhydrous magnesium sulfate and filtered, the solvent was evaporatedunder reduced pressure, the residue was purified by silica gel columnchromatography and the title compound (546 mg) was obtained as lightyellow crystals from the n-hexane:ethyl acetate (5:1) fraction.

¹H NMR (400 MHz, CDCl₃) δ 3.61 (s, 3H), 5.09 (s, 2H), 7.44 (dd, J=1.2,7.6 Hz, 1H), 7.54 (dd, J=7.6, 8.8 Hz, 1H), 7.51 (dd, J=1.2, 8.8 Hz, 1H).

Production Example 19 tert-ButylN-[7-bromo-2-(methoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate

To a suspension of (7-bromo-3-nitropyrazolo[1,5-a]pyridin-2-yl)methylmethyl ether (540 mg) in a mixed solution of ethanol (10 mL), water (5mL) and acetic acid (1 mL) was added zinc powder (540 mg), and thereaction mixture was heated and stirred for 30 minutes at 60° C. Afterfiltering off insoluble residue, water was added to the filtrate,extraction was performed with ethyl acetate and the organic extract waswashed with saturated aqueous sodium bicarbonate and brine. The obtainedorganic extract was dried over anhydrous magnesium sulfate and filtered,the solvent was evaporated under reduced pressure, the residue waspurified by silica gel column chromatography and7-bromo-2-(methoxymethyl)pyrazolo[1,5-a]pyridine-3-amine (371 mg) wasobtained as a brown oil from the n-hexane:ethyl acetate (2:1) fraction.

To a solution of the obtained7-bromo-2-(methoxymethyl)pyrazolo[1,5-a]pyridine-3-amine dissolved intriethylamine (0.303 mL) and dichloromethane (5 mL) was addeddi-tert-butyl dicarbonate (380 mg) while cooling with ice, and thereaction mixture was further stirred overnight at room temperature.Water was added to the reaction mixture, extraction was performed withethyl acetate, and the organic extract was washed with water and brine.The obtained organic extract was dried over anhydrous magnesium sulfateand filtered, the solvent was evaporated under reduced pressure, theresidue was purified by silica gel column chromatography and the titlecompound (360 mg) was obtained as light yellow crystals from then-hexane:ethyl:acetate (5:1) fraction.

¹H NMR (400 MHz, CDCl₃) δ 1.52 (br s, 9H), 3.42 (s, 3H), 4.77 (s, 2H),6.50-6.62 (m, 1H), 6.97 (dd, J=7.2, 8.8 Hz, 1H), 7.04 (dd, J=1.2, 8.8Hz, 1H), 7.58-7.68 (m, 1H).

Similarly to Production Example 7 and 8, the compound of ProductionExample 20 was obtained.

Production Example 20N-[7-Bromo-2-(methoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropylmethyl-N-tetrahydro-2H-4-pyranylmethylamine

Yellow oil

¹H NMR (400 MHz, CDCl₃) δ −0.04-0.04 (m, 2H), 0.30-0.40 (m, 2H),0.72-0.86 (m, 1H), 1.18-1.33 (m, 2H), 1.46-1.62 (m, 1H), 1.64-1.75 (m,2H), 2.87 (d, J=6.8 Hz, 2H), 3.03 (d, J=6.8 Hz, 2H), 3.27 (dt, J=2.0,11.2 Hz, 2H), 3.44 (s, 3H), 3.86-3.96 (m, 2H), 4.67 (s, 2H), 6.89 (dd,J=1.4, 6.8 Hz, 1H), 7.02 (dd, J=6.8, 8.8 Hz, 1H), 7.54 (dd, J=1.4, 8.8Hz, 1H).

Production Example 21 7-Bromo-2-methoxypyrazolo[1,5-a]pyridine

A solution of 2-methoxypyrazolo[1,5-a]pyridine (Reference; Bull. Chem.Soc. Japan, vol. 49(7), 1980-1984 (1976)) (7.15 g) in tetrahydrofuran(140 mL) was cooled to −78° C. under a nitrogen stream, and after addingn-butyllithium (1.6M hexane solution: 46 mL) dropwise thereto, thereaction mixture was stirred for 30 minutes. A solution of1,2-dibromo-1,1,2,2-tetrachloroethane (18.9 g) in tetrahydrofuran (30mL) was added dropwise to the reaction mixture at −78° C., and stirringwas continued for 1 hour. The reaction mixture was raised to roomtemperature, water was added, and then extraction was performed withethyl acetate. The organic extract was washed with brine, dried overanhydrous magnesium sulfate and filtered, the solvent was evaporatedunder reduced pressure, the residue was purified by silica gel columnchromatography and the title compound (7.1 g) was obtained as a yellowoil from the n-hexane:ethyl acetate (50:1) fraction.

¹H NMR (400 MHz, CDCl₃) δ 4.03 (s, 3H), 6.02 (s, 1H), 6.91-6.97 (m, 2H),7.31 (dd, J=2.4, 7.6 Hz, 1H).

Production Example 22 7-Bromo-2-methoxypyrazolo[1,5-a]pyridine-3-amine

To a solution of 7-bromo-2-methoxypyrazolo[1,5-a]pyridine (1 g)dissolved in acetic acid (10 mL) was added an aqueous solution (5 mL) ofsodium nitrite (334 mg), and the reaction mixture was stirred for 20minutes at room temperature. After adding ethanol (60 mL) and water (30mL) to the reaction mixture, zinc powder (1 g) was added and thereaction mixture was heated and stirred for 30 minutes at 60° C. Thereaction mixture was filtered through celite to remove insolubleresidue, water was added and extraction was performed with ethylacetate. The organic extract was washed with brine, dried over anhydrousmagnesium sulfate and filtered, the solvent was evaporated under reducedpressure, the residue was purified by silica gel column chromatographyand the title compound (750 mg) was obtained as brown crystals from then-hexane:ethyl:acetate (3:1) fraction.

¹H NMR (400 MHz, CDCl₃) δ 4.13 (s, 3H), 6.78 (dd, J=1.6, 6.8 Hz, 1H),6.81 (dd, J=6.8, 8.4 Hz, 1H), 7.24 (dd, J=1.6, 8.4 Hz, 1H). ProductionExample 23

tert-Butyl N-(7-bromo-2-methoxypyrazolo[1,5-a]pyridin-3-yl)carbamate

To a solution of 7-bromo-2-methoxypyrazolo[1,5-a]pyridine-3-amine (810mg) dissolved in dichloromethane (20 mL) was added triethylamine (0.7mL) and di-tert-butyl dicarbonate (923 μL) while cooling with ice, andthe reaction mixture was stirred overnight at room temperature. Waterwas added to the obtained reaction mixture, extraction was performedwith ethyl acetate, and the organic extract was washed with brine. Theobtained organic extract was dried over anhydrous magnesium sulfate andfiltered, the solvent was evaporated under reduced pressure, the residuewas purified by silica gel column chromatography and the title compound(1.05 g) was obtained as yellow crystals from the n-hexane:ethyl acetate(10:1) fraction.

¹H NMR (400 MHz, CDCl₃) δ 1.49 (s, 9H), 4.12 (s, 3H), 6.89 (dd, J=1.2,7.6 Hz, 1H), 6.94 (dd, J=7.6, 8.8 Hz, 1H), 7.30-7.39 (m, 1H).

Production Example 24N-(7-Bromo-2-methoxypyrazolo[1,5-a]pyridin-3-yl)-N-cyclopropylmethyl-N-tetrahydro-2H-4-pyranylmethylamine

Sodium hydride (60% in oil; 24.6 mg) was added to a solution oftert-butyl N-(7-bromo-2-methoxypyrazolo[1,5-a]pyridin-3-yl)carbamate(140 mg) in N,N-dimethylformamide (10 mL) at room temperature and thereaction mixture was stirred for 30 minutes. (Bromomethyl)cyclopropane(0.06 mL) was added thereto at the same temperature, and the reactionmixture was stirred for 1 hour at 60° C. After completion of thereaction, the reaction mixture was gradually added to ice, extractionwas performed with ethyl acetate, the organic extract was washed withwater and brine, dried over anhydrous magnesium sulfate and filtered,and the solvent was evaporated under reduced pressure to afford a crudeproduct of tert-butylN-(7-bromo-2-methoxypyrazolo[1,5-a]pyridin-3-yl)-N-cyclopropylmethylcarbamate.

The obtained crude product of tert-butylN-(7-bromo-2-methoxypyrazolo[1,5-a]pyridin-3-yl)-N-cyclopropylmethylcarbamatewas dissolved in ethyl acetate (10 mL) without purification, and then 4Nhydrochloric acid/ethyl acetate (15 mL) was added and the reactionmixture was stirred for 2 hours at room temperature. After completion ofthe reaction, a 5N aqueous sodium hydroxide solution was added to thereaction mixture while cooling with ice for neutralization. Ethylacetate was added, and the obtained organic extract was washed withwater and brine, dried over anhydrous magnesium sulfate and filtered,and the solvent was evaporated under reduced pressure to afford a crudeproduct ofN-(7-bromo-2-methoxypyrazolo[1,5-a]pyridin-3-yl)-N-cyclopropylmethylamine.

The obtained crude product ofN-(7-bromo-2-methoxypyrazolo[1,5-a]pyridin-3-yl)-N-cyclopropylmethylaminewas dissolved in tetrahydrofuran (10 mL) without further purification,and then tetrahydropyran-4-carbaldehyde (233 mg) was added thereto atroom temperature and sodium triacetoxyborohydride (433 mg) was graduallyadded. After stirring the reaction mixture for 2 hours, to the reactionmixture was added saturated aqueous sodium bicarbonate. After whichextraction was performed with ethyl acetate, the organic extract waswashed with brine and dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (10 g) and the title compound (110mg) was obtained as a yellow oil from the ethyl acetate:n-hexane (1:6)fraction.

¹H NMR (400 MHz, CDCl₃) δ −0.02-0.10 (m, 2H), 0.20-0.40 (m, 2H),0.70-0.90 (m, 1H), 1.10-1.39 (m, 2H), 1.40-1.60 (m, 1H), 1.62-1.80 (m,2H), 2.81 (d, J=6.4 Hz, 2H), 2.95 (d, J=7.2 Hz, 2H), 3.27 (dt, J=2.0,12.0 Hz, 2H), 3.80-4.00 (m, 2H), 4.11 (s, 3H), 6.80-6.95 (m, 2H), 7.33(dd, J=1.6, 8.4 Hz, 1H).

Production Example 25 tert-ButylN-[2-methylthiopyrazolo[1,5-a]pyridin-3-yl]carbamate

To a suspension of 2-methylthio-3-nitropyrazolo[1,5-a]pyridine(Reference; Heterocycles, 1977, 6, 379) (400 mg) in ethanol (20 mL),water (10 mL), acetic acid (2 mL) was added zinc powder (800 mg) and thereaction mixture was heated and stirred for 30 minutes at 80° C. Theinsoluble residue was filtered out, water was added to the filtrate andextraction was performed with ethyl acetate, and then the organicextract was washed with saturated aqueous sodium bicarbonate and brine.The organic extract was dried over anhydrous magnesium sulfate andfiltered, and the solvent was evaporated under reduced pressure toafford (2-methylthiopyrazolo[1,5-a]pyridin-3-yl)amine as a crudeproduct.

To a solution of the obtained crude(2-methylthiopyrazolo[1,5-a]pyridin-3-yl)amine dissolved indichloromethane (5 mL) was added triethylamine (0.4 mL) and thendi-tert-butyl dicarbonate (625 mg) while cooling with ice and thereaction mixture was stirred overnight at room temperature. Water wasadded to the reaction mixture, extraction was performed twice with ethylacetate, and the organic extract was washed with water and brine. Theobtained organic extract was dried over anhydrous magnesium sulfate andfiltered, the solvent was evaporated under reduced pressure, the residuewas purified by silica gel column chromatography and the title compound(230 mg) was obtained as a yellow oil from the n-hexane:ethyl acetate(5:1) fraction.

¹H NMR (400 MHz, CDCl₃) δ 1.53 (br s, 9H), 2.60 (s, 3H), 6.00-6.15 (m,1H), 6.69 (t, J=6.8 Hz, 1H), 7.11 (t, J=8.0 Hz, 1H), 7.40-7.50 (m, 1H),8.83 (d, J=6.8 Hz, 1H).

Production Example 26 tert-ButylN-[7-iodo-2-methylthiopyrazolo[1,5-a]pyridin-3-yl]carbamate

To a solution of tert-butylN-[2-methylthiopyrazolo[1,5-a]pyridin-3-yl]carbamate (21.6 g) dissolvedin tetrahydrofuran (1 L) was n-butyllithium (1.6M hexane solution; 130mL) dropwise at −78° C. under a nitrogen stream, and the reactionmixture was stirred for 30 minutes. A solution of 1,2-diiodoethane (24g) in tetrahydrofuran (50 mL) was added to the obtained reactionmixture, and stirring was continued for 1 hour. After adding saturatedaqueous ammonium chloride to the reaction mixture, the temperature wasraised to room temperature, extraction was performed with ethyl acetateand the organic extract was washed with water and brine. The obtainedorganic extract was dried over anhydrous magnesium sulfate and filtered,the solvent was evaporated under reduced pressure, the residue waspurified by silica gel column chromatography and the title compound(21.5 g) was obtained as yellow crystals from the n-hexane:ethyl acetate(5:1) fraction.

¹H NMR (400 MHz, CDCl₃) δ 1.52 (s, 9H), 2.64 (s, 3H), 6.02-6.10 (m, 1H),6.81 (dd, J=7.2, 8.8 Hz, 1H), 7.22 (dd, J=1.2, 7.2 Hz, 1H), 7.42-7.50(m, 1H).

Production Example 27N-Cyclopropylmethyl-N-[7-iodo-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

To a solution of tert-butylN-[7-iodo-2-methylthiopyrazolo[1,5-a]pyridin-3-yl]carbamate (600 mg) inN,N-dimethylformamide (6 mL) was added sodium hydride (60% in oil; 80mg) with ice bath, and the reaction mixture was stirred for 30 minutesat room temperature. (Bromomethyl)cyclopropane (0.22 mL) was added tothe reaction mixture at the same temperature, and stirring was continuedfor 1 hour at 40° C. After completion of the reaction, the reactionmixture was gradually added to ice, extraction was performed with ethylacetate, and the organic extract was washed with water and brine. Theorganic extract was dried over anhydrous magnesium sulfate and thesolvent was evaporated under reduced pressure to afford a crude productof tert-butylN-cyclopropylmethyl-N-[7-iodo-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate.

To a solution of the crude tert-butylN-cyclopropylmethyl-N-[7-iodo-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]carbamatedissolved in ethyl acetate (1 mL) was added 4N hydrochloric acid/ethylacetate (10 mL), and the reaction mixture was stirred for 2 hours atroom temperature. After completion of the reaction, saturated aqueoussodium bicarbonate was added to the reaction mixture while cooling withice for neutralization. The reaction mixture was extracted with ethylacetate, and after washing the organic extract with water and brine, itwas dried over anhydrous magnesium sulfate and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (20 g) and the title compound (506 mg) wasobtained as a yellow oil from the ethyl acetate:n-hexane (1:3) fraction.

¹H NMR (400 MHz, CDCl₃) δ 0.16-0.24 (m, 2H), 0.48-0.56 (m, 2H),1.00-1.10 (m, 1H), 2.60 (s, 3H), 2.96 (d, J=6.0 Hz, 2H), 3.00-3.24 (m,1H), 6.68 (ddd, J=1.2, 6.8, 8.8 Hz, 1H), 7.17 (dd, J=1.2, 6.8 Hz, 1H),7.43 (dd, J=1.2, 8.8 Hz, 1H).

Production Example 28N-Cyclopropylmethyl-N-[7-iodo-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

To a solution ofN-cyclopropylmethyl-N-[7-iodo-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine(70 mg) in tetrahydrofuran (2.5 mL) was addedtetrahydropyran-4-carbaldehyde (56 mg) at room temperature, and thensodium triacetoxyborohydride (103 mg) was gradually added. After 1 hour,saturated aqueous sodium bicarbonate was added, extraction was performedwith ethyl acetate, the extract was washed with brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure to afford a crude product of the title compound (50 mg)as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ−0.06-0.04 (m, 2H), 0.30-0.38 (m, 2H),0.74-0.86 (m, 1H), 1.20-1.32 (m, 2H), 1.40-1.60 (m, 1H), 1.66-1.80 (m,2H), 2.69 (s, 3H), 2.85 (d, J=6.8 Hz, 2H), 3.02 (d, J=7.2 Hz, 2H),3.22-3.32 (m, 2H), 3.86-3.94 (m, 2H), 6.72 (dd, J=7.2, 8.8 Hz, 1H), 7.15(dd, J=1.2, 7.2 Hz, 1H), 7.40 (dd, J=1.2, 8.8 Hz, 1H).

Production Example 29 2,6-Dimethoxy-4-(methoxymethyl)phenylboric acid

To a solution of 3,5-dimethoxy(methoxymethyl)benzene (23.7 g) intetrahydrofuran (500 mL) was added n-butyllithium (1.56M hexanesolution; 100 mL) at −78° C., and the reaction mixture was stirred for30 minutes while cooling with ice. After cooling the internaltemperature of the obtained reaction mixture to −78° C., to a reactionmixture was added triisopropoxyborane (39 mL), and the internaltemperature was raised to room temperature while stirring. Aftercompletion of the reaction, saturated aqueous ammonium chloride wasadded to the reaction mixture while cooling with ice, and then ethylacetate was added to the reaction mixture, the organic extract waswashed with brine and dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography and the title compound (7.5 g) wasobtained as a yellow oil from the ethyl acetate fraction.

¹H NMR (400 MHz, CDCl₃) δ 3.43 (s, 3H), 3.92 (s, 6H), 4.47 (s, 2H), 6.61(s, 2H), 7.18 (s, 2H).

Production Example 30 4-(Hydroxymethyl)-2,6-dimethoxyphenylboric acid

To a solution of 3,5-dimethoxybenzyl alcohol (2.71 g) in tetrahydrofuran(50 mL) was added n-butyllithium (1.56M hexane solution; 36.2 mL) whilecooling with ice with ice bath, and the internal temperature was raisedto room temperature and stirred for 1 hour. The internal temperature wasthen cooled to −78° C., to the mixture was added triethoxyborane (9.6mL), and the temperature was raised to room temperature while stirring.After completion of the reaction, saturated aqueous ammonium chloridewas added to the reaction mixture while cooling with ice and thereaction mixture was extracted with ethyl acetate, and then afterwashing the organic extract with brine, it was dried over anhydrousmagnesium sulfate and the solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography (50 g) andthe title compound (1.72 g) was obtained as a white amorphous solid fromthe ethyl acetate fraction.

¹H NMR (400 MHz, CDCl₃) δ 3.92 (s, 6H), 4.73 (s, 2H), 6.65 (s, 2H), 7.18(s, 2H).

Similarly to Production Example 30, the compounds of Production Example31 and 32 were synthesized.

Production Example 31 4-(2-Hydroxyethyl)-2,6-dimethoxyphenylboric acid

Yellow oil

¹H NMR (400 MHz, CDCl₃) δ 1.56-1.62 (m, 1H), 2.88 (t, J=6.4 Hz, 2H),3.88-3.92 (m, 2H), 3.90 (s, 6H), 6.51 (s, 2H), 7.14 (s, 2H).

Production Example 32 4-(3-Hydroxypropyl)-2,6-dimethoxyphenylboric acid

¹H NMR (400 MHz, CDCl₃) δ 1.84-1.94 (m, 2H), 2.68-2.76 (m, 2H),3.64-3.74 (m, 2H), 3.90 (s, 6H), 6.48 (s, 2H), 7.16 (s, 2H).

Similarly to Production Example 29, the compounds of Production Example33 to 35 were synthesized.

Production Example 33 4-(Ethoxymethyl)-2,6-dimethoxyphenylboric acid

¹H NMR (400 MHz, CDCl₃) δ 1.28 (t, J=7.1 Hz, 3H), 3.58 (q, J=7.1 Hz,2H), 3.92 (s, 6H), 4.51 (s, 2H), 6.63 (s, 2H), 7.19 (s, 2H).

Production Example 344-[1-[1-(tert-Butyl)-1,1-dimethylsilyl]oxyethyl]-2,6-dimethoxyphenylboricacid

Colorless oil

¹H NMR (400 MHz, CDCl₃) δ 0.01 (s, 3H), 0.08 (s, 3H), 0.92 (s, 9H), 1.41(d, J=6.4 Hz, 3H), 3.90 (s, 6H), 4.84 (q, J=6.4 Hz, 1H), 6.61 (s, 2H),7.17 (s, 2H).

Production Example 35 2,4-Dimethoxy-6-(methoxymethyl)phenylboric acid

White crystals

¹H NMR (400 MHz, CDCl₃) δ 3.41 (s, 3H), 3.85 (s, 3H), 3.88 (s, 3H), 4.53(s, 2H), 6.48 (d, J=2.4 Hz, 1H), 6.55 (d, J=2.4 Hz, 1H), 7.09 (br s,2H).

Example 1N-Cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine

To a solution ofN-(7-bromo-2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-cyclopropylmethyl-N-tetrahydro-2H-4-pyranylmethylamine(60 mg) dissolved in 1,2-dimethoxyethane (2 mL) and water (1 mL) wasadded 2,6-dimethoxy-4-(methoxymethyl)phenylboric acid (45 mg),tetrakis(triphenylphosphine)palladium(0) (35 mg) and barium hydroxideoctahydrate (72 mg), and the reaction mixture was heated and stirred for4 hours at 90° C. The reaction mixture was then cooled to roomtemperature, water and ethyl acetate were added, the reaction mixturewas filtered through celite to remove insoluble residue, and thefiltrate was extracted with ethyl acetate. The combined organic extractwas washed with brine, dried over anhydrous magnesium sulfate andfiltered, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography and the titlecompound (40 mg) was obtained as light yellow crystals from then-hexane:ethyl acetate (1:1) fraction.

¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 2H), 0.34-0.38 (m, 2H),0.80-0.90 (m, 1H), 1.22 (t, J=7.6 Hz, 3H), 1.24-1.34 (m, 2H), 1.54-1.64(m, 1H), 1.74-1.80 (m, 2H), 2.77 (q, J=7.6 Hz, 2H), 2.88 (d, J=6.8 Hz,2H), 3.05 (d, J=7.2 Hz, 2H), 3.31 (t, J=11.6 Hz, 2H), 3.49 (s, 3H), 3.73(s, 6H), 3.90-4.00 (m, 2H), 4.53 (s, 2H), 6.59 (dd, J=1.2, 6.8 Hz, 1H),6.67 (s, 2H), 7.00 (dd, J=6.8, 8.8 Hz, 1H), 7.44 (dd, J=1.2, 8.8 Hz,1H).

Example 1-2N-Cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine

The title compound (29 g) was recrystallized from ethanol (80 mL) toafford light yellow crystals (27.5 g).

¹H NMR (600 MHz, DMSO-d₆) δ −0.02-0.00 (m, 2H), 0.32-0.35 (m, 2H),0.73-0.79 (m, 1H), 1.11-1.19 (m, 5H), 1.51-1.57 (m, 1H), 1.69-1.72 (brdd, J=2.0, 12.7 Hz, 2H), 2.65 (q, J=7.6 Hz, 2H), 2.84 (d, J=6.8 Hz, 2H),3.01 (d, J=7.1 Hz, 2H), 3.21 (ddd, J=1.7, 11.7, 11.7 Hz, 2H), 3.39 (s,3H), 3.63 (s, 6H), 3.82 (br dd, J=2.4, 11.5 Hz, 2H), 4.49 (s, 2H), 6.55(dd, J=1.2, 6.8 Hz, 1H), 6.74 (s, 2H), 7.06 (dd, J=6.6, 8.8 Hz, 1H),7.51 (dd, J=1.2, 8.8 Hz, 1H).

Similarly to Example 1, the compounds of Example 2 to 9 weresynthesized.

Example 2N-Cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(1-methoxyethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine

Light yellow crystals

¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 2H), 0.32-0.38 (m, 2H),0.80-0.92 (m, 1H), 1.23 (t, J=7.6 Hz, 3H), 1.22-1.34 (m, 2H), 1.52 (d,J=6.4 Hz, 3H), 1.52-1.64 (m, 1H), 1.72-1.82 (m, 2H), 2.79 (q, J=7.6 Hz,2H), 2.89 (d, J=6.4 Hz, 2H), 3.05 (d, J=7.2 Hz, 2H), 3.26-3.34 (m, 2H),3.36 (s, 3H), 3.73 (s, 6H), 3.90-3.98 (m, 2H), 4.34 (q, J=6.8 Hz, 1H),6.61 (dd, J=1.2, 6.8 Hz, 1H), 6.64 (d, J=2.8 Hz, 2H), 7.01 (dd, J=6.8,8.8 Hz, 1H), 7.44 (dd, J=1.2, 8.8 Hz, 1H).

Example 3N-Cyclopropylmethyl-N-7-[4-(ethoxymethyl)-2,6-dimethoxyphenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine

Yellow crystals

¹H NMR (400 MHz, CDCl₃) δ −0.02-0.06 (m, 2H), 0.34-0.43 (m, 2H),0.80-0.94 (m, 1H), 1.24 (t, J=7.5 Hz, 3H), 1.33 (t, J=7.0 Hz, 3H),1.20-1.38 (m, 2H), 1.54-1.68 (m, 1H), 1.74-1.84 (m, 2H), 2.78 (q, J=7.5Hz, 2H), 2.90 (d, J=6.6 Hz, 2H), 3.07 (d, J=7.0 Hz, 2H), 3.33 (dt,J=1.6, 12.0 Hz, 2H), 3.66 (q, J=7.0 Hz, 2H), 3.75 (s, 6H), 3.92-4.02 (m,2H), 4.59 (s, 2H), 6.61 (br d, J=6.8 Hz, 1H), 6.71 (s, 2H), 7.03 (dd,J=7.0, 8.8 Hz, 1H), 7.46 (br d, J=8.8 Hz, 1H).

Example 4N-Cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-3-furanylmethylamine

Yellow oil

¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 2H), 0.32-0.42 (m, 2H),0.80-0.82 (m, 1H), 1.21 (t, J=7.6 Hz, 3H), 1.58-1.66 (m, 1H), 1.84-1.94(m, 1H), 2.20-2.32 (m, 1H), 2.74 (q, J=7.6 Hz, 2H), 2.90 (d, J=6.4 Hz,2H), 3.40-3.50 (m, 1H), 3.18-3.26 (m, 1H), 3.47 (s, 3H), 3.58-3.70 (m,2H), 3.71 (s, 6H), 3.72-3.82 (m, 2H), 4.51 (s, 2H), 6.58 (dd, J=0.8, 6.8Hz, 1H), 6.66 (s, 2H), 7.00 (ddd, J=0.2, 6.8, 8.8 Hz, 1H), 7.42 (dd,J=0.6, 8.8 Hz, 1H).

Example 5(4-3-[(cyclopropylmethyl)(tetrahydro-2H-4-pyranylmethyl)amino]-2-ethylpyrazolo[1,5-a]pyridin-7-yl-3,5-dimethoxyphenyl)methanol

Light yellow amorphous solid

¹H NMR (400 MHz, CDCl₃) δ −0.03-0.05 (m, 2H), 0.32-0.40 (m, 2H),0.80-0.90 (m, 1H), 1.22 (t, J=7.5 Hz, 3H), 1.22-1.35 (m, 2H), 1.53-1.66(m, 1H), 1.72-1.81 (m, 2H), 1.96 (t, J=5.6 Hz, 1H), 2.78 (q, J=7.5 Hz,2H), 2.86-2.92 (m, 2H), 3.02-3.09 (m, 2H), 3.28-3.38 (m, 2H), 3.74 (s,6H), 3.90-4.00 (m, 2H), 4.76 (d, J=5.6 Hz, 2H), 6.61 (dd, J=1.3, 6.8 Hz,1H), 6.72 (s, 2H), 7.02 (dd, J=6.8, 8.8 Hz, 1H), 7.46 (dd, J=1.3, 8.8Hz, 1H).

Example 6(4-3-[(Cyclobutylmethyl)(tetrahydro-2H-4-pyranylmethyl)amino]-2-ethylpyrazolo[1,5-a]pyridin-7-yl-3,5-dimethoxyphenyl)methanol

Light yellow amorphous solid

¹H NMR (400 MHz, CDCl₃) δ 1.19-1.32 (m, 2H), 1.21 (t, J=7.5 Hz, 3H),1.51-1.64 (m, 3H), 1.70-1.95 (m, 6H), 2.01 (t, J=5.6 Hz, 1H), 2.26-2.39(m, 1H), 2.73 (q, J=7.5 Hz, 2H), 2.90-2.97 (m, 2H), 3.02-3.08 (m, 2H),3.26-3.37 (m, 2H), 3.73 (s, 6H), 3.89-3.99 (m, 2H), 4.74 (d, J=5.6 Hz,2H), 6.60 (dd, J=1.3, 6.8 Hz, 1H), 6.71 (s, 2H), 7.02 (dd, J=6.8, 8.8Hz, 1H), 7.41 (dd, J=1.3, 8.8 Hz, 1H).

Example 72-(4-3-[(Cyclopropylmethyl)(tetrahydro-2H-4-pyranylmethyl)amino]-2-ethylpyrazolo[1,5-a]pyridin-7-yl-3,5-dimethoxyphenyl)-1-ethanol

Light green oil

¹H NMR (400 MHz, CDCl₃) δ −0.04-0.02 (m, 2H), 0.32-0.38 (m, 2H),0.78-0.88 (m, 1H), 1.21 (t, J=7.6 Hz, 3H), 1.22-1.32 (m, 2H), 1.52-1.65(m, 2H), 1.72-1.80 (m, 2H), 2.75 (q, J=7.6 Hz, 2H), 2.87 (d, J=6.8 Hz,2H), 2.92 (t, J=6.4 Hz, 2H), 3.04 (d, J=7.2 Hz, 2H), 3.26-3.34 (m, 2H),3.70 (s, 6H), 3.90-3.98 (m, 4H), 6.55 (s, 2H), 6.58 (dd, J=1.6, 6.8 Hz,1H), 7.00 (dd, J=6.8, 8.8 Hz, 1H), 7.43 (dd, J=1.6, 8.8 Hz, 1H).

Example 83-(4-3-[(Cyclopropylmethyl)(tetrahydro-2H-4-pyranylmethyl)amino]-2-ethylpyrazolo[1,5-a]pyridin-7-yl-3,5-dimethoxyphenyl)-1-propanol

Yellow oil

¹H NMR (400 MHz, CDCl₃) δ −0.03-0.01 (m, 2H), 0.33-0.37 (m, 2H),0.81-0.85 (m, 1H), 1.19-1.31 (m, 5H), 1.50-1.57 (m, 1H), 1.72-1.77 (m,2H), 1.95-2.04 (m, 2H), 2.73-2.80 (m, 4H), 2.87 (d, J=6.8 Hz, 2H), 3.04(d, J=6.8 Hz, 2H), 3.30 (dt, J=2.0, 12.0 Hz, 2H), 3.70 (s, 6H), 3.76 (t,J=6.4 Hz, 2H), 3.91-3.95 (m, 2H), 6.54 (s, 2H), 6.59 (dd, J=1.2, 6.8 Hz,1H), 7.00 (dd, J=6.8, 8.8 Hz, 1H), 7.43 (dd, J=1.6, 8.8 Hz, 1H).

Example 9N-Cyclopropylmethyl-N-7-[2,4-dimethoxy-6-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine

Light yellow crystals

¹H NMR (400 MHz, CDCl₃) δ −0.04-0.02 (m, 2H), 0.30-0.36 (m, 2H),0.78-0.88 (m, 1H), 1.20 (t, J=7.6 Hz, 3H), 1.20-1.32 (m, 2H), 1.52-1.64(m, 1H), 1.72-1.80 (m, 2H), 2.70-2.80 (m, 2H), 2.87 (d, J=6.8 Hz, 2H),3.04 (d, J=6.8 Hz, 2H), 3.19 (s, 3H), 3.28-3.34 (m, 2H), 3.68 (s, 3H),3.88 (s, 3H), 3.90-3.98 (m, 2H), 3.98 (d, J=12.8 Hz, 1H), 4.21 (d,J=12.8 Hz, 1H), 6.51 (d, J=2.4 Hz, 1H), 6.54 (dd, J=1.6, 6.8 Hz, 1H),6.76 (d, J=2.4 Hz, 1H), 6.99 (dd, J=6.8, 8.8 Hz, 1H), 7.44 (dd, J=1.2,8.8 Hz, 1H).

Example 10 tert-ButylN-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-ylcarbamate

To a solution of tert-butylN-(7-bromo-2-ethylpyrazolo[1,5-a]pyridin-3-yl)carbamate (100 mg)dissolved in 1,2-dimethoxyethane (6 mL) and water (3 mL) was added2,6-dimethoxy-4-(methoxymethyl)phenylboric acid (100 mg),tetrakis(triphenylphosphine)palladium(0) (51 mg) and barium hydroxideoctahydrate (139 mg), and the reaction mixture was heated and stirredfor 3 hours at 80° C. under a nitrogen stream. Water was added to theobtained reaction mixture and extraction was performed with ethylacetate. The organic extract was washed with brine, dried over anhydrousmagnesium sulfate and filtered, and then the solvent was evaporatedunder reduced pressure, the residue was purified by silica gel columnchromatography and the title compound (87 mg) was obtained as a lightyellow amorphous solid from the n-hexane:ethyl acetate (2:1) fraction.

¹H NMR (400 MHz, CDCl₃) δ 1.21 (t, J=7.6 Hz, 3H), 1.54 (br s, 9H), 2.72(q, J=7.6 Hz, 2H), 3.47 (s, 3H), 3.69 (s, 6H), 4.51 (s, 2H), 5.82-5.90(m, 1H), 6.58-6.65 (m, 1H), 6.65 (s, 2H), 7.08-7.14 (m, 1H), 7.32-7.38(m, 1H).

Example 11N-Cyclobutylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine

To a solution of tert-butylN-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-ylcarbamate(43 mg) dissolved in N,N-dimethylformamide (1 mL) was added sodiumhydride (60% in oil; 6 mg), and (bromomethyl)cyclobutane (0.013 mL), andthe mixture was stirred for 1 hour at room temperature. Water was addedto the obtained reaction mixture, which was then extracted with ethylacetate and washed with brine. The obtained organic extract was driedover anhydrous magnesium sulfate and filtered, and the solvent wasevaporated under reduced pressure to obtain a crude product oftert-butylN-cyclobutylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-ylcarbamate.

The obtained crude product of tert-butylN-cyclobutylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-ylcarbamatewas dissolved in ethyl acetate (1 mL) without further purification, andthen 4N hydrochloric acid (ethyl acetate solution; 2 mL) was added andthe mixture was stirred for 1 hour at 40° C. After neutralizing theobtained reaction mixture with 5N aqueous sodium hydroxide while coolingwith ice, extraction was performed with ethyl acetate and the organicextract was washed with brine. It was then dried over anhydrousmagnesium sulfate and filtered, and the solvent was evaporated underreduced pressure to afford a crude product ofN-cyclobutylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-ylamine.

To a solution of the obtained residue dissolved in tetrahydrofuran (1mL) without further purification was addedtetrahydropyran-4-carbaldehyde (33 mg) and sodium triacetoxyborohydride(62 mg), and the mixture was stirred for 1 hour at room temperature.Water and then saturated aqueous sodium bicarbonate were added to theobtained reaction mixture, extraction was performed with ethyl acetate,and the organic extract was washed with brine. It was then dried overanhydrous magnesium sulfate and filtered, the solvent was evaporatedunder reduced pressure, the residue was purified by silica gel columnchromatography and the title compound (24 mg) was obtained as a yellowoil from the n-hexane:ethyl acetate (5:1) fraction.

¹H NMR (400 MHz, CDCl₃) δ 1.21 (t, J=7.6 Hz, 3H), 1.22-1.30 (m, 2H),1.55-1.62 (m, 3H), 1.71-1.80 (m, 4H), 1.81-1.93 (m, 2H), 2.28-2.36 (m,1H), 2.72 (q, J=7.6 Hz, 2H), 2.93 (d, J=6.8 Hz, 2H), 3.04 (d, J=7.2 Hz,2H), 3.27-3.35 (m, 2H), 3.48 (s, 3H), 3.72 (s, 6H), 3.91-3.96 (m, 2H),4.52 (s, 2H), 6.59 (br d, J=6.8 Hz, 1H), 6.67 (s, 2H), 7.01 (dd, J=6.8,8.8 Hz, 1H), 7.40 (br d, J=8.8 Hz, 1H).

Similarly to Example 11, the compounds of Example 12 to 14 weresynthesized.

Example 12N-Butyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine

Yellow oil

¹H NMR (400 MHz, CDCl₃) δ 0.86 (t, J=6.8 Hz, 3H), 1.22 (t, J=7.6 Hz,3H), 1.24-1.40 (m, 6H), 1.50-1.60 (m, 1H), 1.70-1.78 (m, 2H), 2.73 (q,J=7.6 Hz, 2H), 2.96 (d, J=7.2 Hz, 2H), 3.01 (t, J=7.2 Hz, 2H), 3.26-3.35(m, 2H), 3.49 (s, 3H), 3.73 (s, 6H), 3.90-3.97 (m, 2H), 4.53 (s, 2H),6.60 (dd, J=1.2, 6.8 Hz, 1H), 6.68 (s, 2H), 7.01 (dd, J=6.8, 8.8 Hz,1H), 7.42 (dd, J=1.2, 8.8 Hz, 1H).

Example 13N-7-[2,6-Dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-propyl-N-tetrahydro-2H-4-pyranylmethylamine

Light yellow amorphous solid

¹H NMR (400 MHz, CDCl₃) δ 0.87 (t, J=7.6 Hz, 3H), 1.20 (t, J=7.2 Hz,3H), 1.23-1.32 (m, 2H), 1.36-1.45 (m, 2H), 1.52-1.62 (m, 1H), 1.72-1.78(m, 2H), 2.73 (q, J=7.2 Hz, 2H), 2.96-3.00 (m, 4H), 3.27-3.35 (m, 2H),3.49 (s, 3H), 3.73 (s, 6H), 3.90-3.97 (m, 2H), 4.53 (s, 2H), 6.60 (dd,J=1.6, 6.8 Hz, 1H), 6.68 (s, 2H), 7.01 (dd, J=6.8, 8.8 Hz, 1H), 7.42(dd, J=1.6, 8.8 Hz, 1H).

Example 14N-7-[2,6-Dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-isobutyl-N-tetrahydro-2H-4-pyranylmethylamine

Light yellow amorphous solid

¹H NMR (400 MHz, CDCl₃) δ 0.91 (d, J=6.8 Hz, 6H), 1.20 (t, J=7.6 Hz,3H), 1.22-1.31 (m, 2H), 1.50-1.62 (m, 2H), 1.72-1.80 (m, 2H), 2.74 (q,J=7.6 Hz, 2H), 2.82 (d, J=7.2 Hz, 2H), 2.91 (d, J=6.8 Hz, 2H), 3.26-3.34(m, 2H), 3.47 (s, 3H), 3.72 (s, 6H), 3.90-3.96 (m, 2H), 4.52 (s, 2H),6.58 (dd, J=1.6, 6.8 Hz, 1H), 6.66 (s, 2H), 7.00 (dd, J=6.8, 8.8 Hz,1H), 7.43 (dd, J=1.6, 8.8 Hz, 1H).

Example 157-[2,6-Dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridine-3-amine

A suspension of7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethyl-3-nitropyrazolo[1,5-a]pyridine(0.7 g) in a mixed solvent of ethanol (35 mL), water (18 mL) and aceticacid (3.5 mL) was added zinc powder (0.7 g) at room temperature, and thereaction mixture was heated and stirred for 30 minutes at 60° C. Thereaction mixture was filtered through celite to remove insolubleresidue, water was added to the filtrate and extraction was performedwith ethyl acetate. The obtained organic extract was washed with brine,saturated aqueous sodium bicarbonate and then brine and dried overanhydrous magnesium sulfate and filtered, after which the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography and the title compound (0.48 g) was obtainedas a yellow oil from the n-hexane:ethyl acetate (4:1) fraction.

¹H NMR (400 MHz, CDCl₃) δ 1.23 (t, J=7.6 Hz, 3H), 2.60-2.98 (m, 2H),3.47 (s, 3H), 3.70 (s, 6H), 4.51 (s, 2H), 6.40-6.60 (m, 1H), 6.65 (s,2H), 6.90-7.08 (m, 1H), 7.24-7.38 (m, 1H).

MS (ESI) m/z 342 MH⁺

Example 16 tert-ButylN-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-ylcarbamate

To a solution of7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridine-3-amine(0.48 g) dissolved in dichloromethane (4.8 mL) was added triethylamine(0.3 mL) and di-tert-butyl dicarbonate (0.39 mL) at room temperature,and the reaction mixture was stirred overnight at room temperature.Water was added to the obtained reaction mixture and extraction wasperformed with ethyl acetate. The organic extract was washed with brine,dried over anhydrous magnesium sulfate and filtered, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography and the title compound (0.54 g) was obtainedas white crystals from the n-hexane:ethyl acetate (1:1) fraction.

¹H NMR (400 MHz, CDCl₃) δ 1.21 (t, J=7.6 Hz, 3H), 1.54 (br s, 9H), 2.72(q, J=7.6 Hz, 2H), 3.47 (s, 3H), 3.69 (s, 6H), 4.51 (s, 2H), 5.86 (br s,1H), 6.61 (d, J=6.8 Hz, 1H), 6.65 (s, 2H), 7.10 (dd, J=6.8, 8.8 Hz, 1H),7.35 (d, J=8.8 Hz, 1H).

Example 17N-7-[4-(1-[1-(tert-Butyl)-1,1-dimethylsilyl]oxyethyl)-2,6-dimethoxyphenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-cyclopropylmethyl-N-tetrahydro-2H-4-pyranylmethylamine

To a solution ofN-(7-bromo-2-methoxypyrazolo[1,5-a]pyridin-3-yl)-N-cyclopropylmethylamine(70 mg) dissolved in 1,2-dimethoxyethane (4 mL) and water (2 mL) wasadded4-[1-[1-(tert-butyl)-1,1-dimethylsilyl]oxyethyl]-2,6-dimethoxyphenylboricacid (92 mg), tetrakis(triphenylphosphine)palladium(0) (31 mg) andbarium hydroxide octahydrate (85 mg), and the mixture was heated andstirred for 1 hour at 80° C. under a nitrogen stream. Ethyl acetate wasadded to the reaction mixture, and after filtering off the insolubleresidue, extraction was performed with ethyl acetate and the organicextract was washed with brine. The obtained organic extract was driedover anhydrous magnesium sulfate and filtered, the solvent wasevaporated under reduced pressure, the residue was purified by silicagel column chromatography and the title compound (112 mg) was obtainedas a yellow oil from the n-hexane:ethyl acetate (4:1) fraction.

¹H NMR (400 MHz, CDCl₃) δ −0.07-0.03 (m, 2H), 0.07 (s, 3H), 0.12 (s,3H), 0.32-0.38 (m, 2H), 0.79-0.88 (m, 1H), 0.96 (s, 9H), 1.21-1.33 (m,2H), 1.26 (t, J=7.2 Hz, 3H), 1.49 (d, J=6.4 Hz, 3H), 1.51-1.63 (m, 1H),1.70-1.80 (m, 2H), 2.77 (q, J=7.2 Hz, 2H), 2.84-2.91 (m, 2H), 3.00-3.07(m, 2H), 3.25-3.35 (m, 2H), 3.70 (s, 6H), 3.89-3.97 (m, 2H), 4.92 (q,J=6.4 Hz, 1H), 6.61 (dd, J=1.3, 6.8 Hz, 1H), 6.67 (s, 1H), 6.68 (s, 1H),7.00 (dd, J=6.8, 8.8 Hz, 1H), 7.43 (dd, J=1.3, 8.8 Hz, 1H).

Example 181-(4-3-[(Cyclopropylmethyl)(tetrahydro-2H-4-pyranylmethyl)amino]-2-ethylpyrazolo[1,5-a]pyridin-7-yl-3,5-dimethoxyphenyl)-1-ethanol

To a solution ofN-[7-[4-[1-[1-(tert-butyl)-1,1-dimethylsilyl]oxyethyl]-2,6-dimethoxyphenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropylmethyl-N-tetrahydro-2H-4-pyranylmethylamine(112 mg) dissolved in tetrahydrofuran (1 mL) was addedtetrabutylammonium fluoride (1M tetrahydrofuran solution; 0.27 mL) atroom temperature, and the reaction mixture was stirred for 3 hours atthe same temperature. After adding saturated aqueous ammonium chlorideto the obtained reaction mixture, extraction was performed with ethylacetate, the organic extract was washed with brine, dried over anhydrousmagnesium sulfate and filtered, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography and the title compound (66 mg) was obtained as a lightyellow amorphous solid from the n-hexane:ethyl acetate (1:2) fraction.

¹H NMR (400 MHz, CDCl₃) δ −0.04-0.12 (m, 2H), 0.32-0.38 (m, 2H),0.78-0.88 (m, 1H), 1.21 (t, J=7.5 Hz, 3H), 1.21-1.33 (m, 2H), 1.50-1.65(m, 4H), 1.70-1.80 (m, 2H), 2.76 (q, J=7.5 Hz, 2H), 2.84-2.91 (m, 2H),3.01-3.08 (m, 2H), 3.26-3.37 (m, 2H), 3.73 (s, 6H), 3.88-3.98 (m, 2H),4.91-4.99 (m, 1H), 6.59 (dd, J=1.3, 6.8 Hz, 1H), 6.70 (s, 1H), 6.74 (s,1H), 7.01 (dd, J=6.8, 8.8 Hz, 1H), 7.45 (dd, J=1.3, 8.8 Hz, 1H).

Example 194-3-[(Cyclopropylmethyl)(tetrahydro-2H-4-pyranylmethyl)amino]-2-ethylpyrazolo[1,5-a]pyridin-7-yl-3,5-dimethoxybenzaldehyde

To a solution of(4-3-[(cyclopropylmethyl)(tetrahydro-2H-4-pyranylmethyl)amino]-2-ethylpyrazolo[1,5-a]pyridin-7-yl-3,5-dimethoxyphenyl)methanol(50 mg) in acetone (2 mL) was added activated manganese(IV) oxide (250mg) at room temperature, and the reaction mixture was stirred for 12hours. The manganese oxide was filtered out from the reaction mixtureand the filtrate was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography and the title compound (41mg) was obtained as a yellow solid from the ethyl acetate:n-hexane (1:2)fraction.

¹H NMR (400 MHz, CDCl₃) δ −0.02-0.01 (m, 2H), 0.30-0.40 (m, 2H),0.80-0.88 (m, 1H), 1.18-1.32 (m, 5H), 1.54-1.62 (m, 1H), 1.72-1.80 (m,2H), 2.75 (q, J=7.6 Hz, 2H), 2.88 (d, J=6.8 Hz, 2H), 3.05 (d, J=6.8 Hz,2H), 3.25-3.34 (m, 2H), 3.79 (s, 6H), 3.93-3.98 (m, 2H), 6.61 (dd,J=1.2, 6.8 Hz, 1H), 7.03 (dd, J=6.8, 8.8 Hz, 1H), 7.21 (s, 2H), 7.49(dd, J=1.2, 8.8 Hz, 1H), 10.02 (s, 1H).

Example 20N-Butyl-N-7-[4-(ethoxymethyl)-2,6-dimethoxyphenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine

N-(7-Bromo-2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-butyl-N-tetrahydro-2H-4-pyranylmethylamine(150 mg) and 4-(hydroxymethyl)-2,6-dimethoxyphenylboric acid (250 mg)were reacted with the same manner as Example 1 to afford(4-3-[butyl(tetrahydro-2H-4-pyranylmethyl)amino]-2-ethylpyrazolo[1,5-a]pyridin-7-yl-3,5-dimethoxyphenyl)methanol(189 mg) as a yellow oil.

To a solution of the obtained(4-3-[butyl(tetrahydro-2H-4-pyranylmethyl)amino]-2-ethylpyrazolo[1,5-a]pyridin-7-yl-3,5-dimethoxyphenyl)methanol(189 mg) in N,N-dimethylformamide (15 mL) was added sodium hydride (60%oil; 24 mg) at room temperature, and the reaction mixture was stirredfor 30 minutes. Next, to the resulting mixture was added iodoethane(0.047 mL), and the mixture was stirred for 1 hour at 60° C. Aftercompletion of the reaction, ice was added to the reaction mixture whilecooling with ice, extraction was performed with ethyl acetate and theorganic extract was washed with brine and dried over anhydrous magnesiumsulfate, after which the solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography (10 g) andthe title compound (111 mg) was obtained as yellow crystals from theethyl acetate:n-hexane (1:2) fraction.

¹H NMR (400 MHz, CDCl₃) δ 0.86 (t, J=7.0 Hz, 3H), 1.20 (t, J=7.5 Hz,3H), 1.31 (t, J=7.0 Hz, 3H), 1.17-1.42 (m, 6H), 1.50-1.64 (m, 1H),1.70-1.79 (m, 2H), 2.73 (q, J=7.5 Hz, 2H), 2.96 (d, J=7.0 Hz, 2H), 3.01(t, J=7.0 Hz, 2H), 3.33 (dt, J=1.6, 12.0 Hz, 2H), 3.64 (q, J=7.0 Hz,2H), 3.72 (s, 6H), 3.90-4.00 (m, 2H), 4.57 (s, 2H), 6.59 (dd, J=1.1, 6.8Hz, 1H), 6.69 (s, 2H), 7.01 (dd, J=6.9, 8.9 Hz, 1H), 7.42 (dd, J=1.3,8.8 Hz, 1H).

Similarly to Example 20, the compounds of Example 21 to 27 weresynthesized.

Example 21N-Cyclopropylmethyl-N-(7-2,6-dimethoxy-4-[(2-piperidinoethoxy)methyl]phenyl-2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-tetrahydro-2H-4-pyranylmethylamine

Yellow oil

¹H NMR (400 MHz, CDCl₃) δ −0.05-0.02 (m, 2H), 0.32-0.38 (m, 2H),0.80-0.88 (m, 1H), 1.18-1.32 (m, 5H), 1.40-1.48 (m, 2H), 1.52-1.68 (m,5H), 1.70-1.78 (m, 2H), 2.40-2.55 (m, 4H), 2.64 (t, J=6.0 Hz, 2H), 2.76(q, J=7.2 Hz, 2H), 2.87 (d, J=6.8 Hz, 2H), 3.04 (d, J=6.8 Hz, 2H), 3.31(t, J=11.2 Hz, 2H), 3.68 (t, J=6.4 Hz, 2H), 3.71 (s, 6H), 3.90-3.97 (m,2H), 4.59 (s, 2H), 6.58 (dd, J=0.8, 6.8 Hz, 1H), 6.68 (s, 2H), 7.00 (dd,J=6.8, 8.4 Hz, 1H), 7.44 (br d, J=8.8 Hz, 1H).

Example 22N-Cyclopropylmethyl-N-(7-2,6-dimethoxy-4-[(2-methoxyethoxy)methyl]phenyl-2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-tetrahydro-2H-4-pyranylmethylamine

Yellow oil

¹H NMR (400 MHz, CDCl₃) δ −0.02-0.01 (m, 2H), 0.30-0.38 (m, 2H),0.80-0.90 (m, 1H), 1.19-1.30 (m, 5H), 1.50-1.62 (m, 1H), 1.72-1.80 (m,2H), 2.75 (q, J=7.6 Hz, 2H), 2.87 (d, J=6.8 Hz, 2H), 3.04 (d, J=6.8 Hz,2H), 3.25-3.35 (m, 2H), 3.43 (s, 3H), 3.62-3.65 (m, 2H), 3.71-3.73 (m,8H), 3.90-3.98 (m, 2H), 4.64 (s, 2H), 6.57 (dd, J=1.6, 6.8 Hz, 1H), 6.70(s, 2H), 7.00 (dd, J=6.8, 9.2 Hz, 1H), 7.44 (dd, J=1.2, 8.8 Hz, 1H).

Example 23N-7-[4-(Ethoxymethyl)-2,6-dimethoxyphenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-propyl-N-tetrahydro-2H-4-pyranylmethylamine

Yellow oil

¹H NMR (400 MHz, CDCl₃) δ 0.87 (t, J=7.4 Hz, 3H), 1.20 (t, J=7.5 Hz,3H), 1.31 (t, J=7.0 Hz, 3H), 1.18-1.33 (m, 2H), 1.34-1.47 (m, 2H),1.50-1.65 (m, 1H), 1.70-1.80 (m, 2H), 2.74 (q, J=7.5 Hz, 2H), 2.96 (d,J=7.1 Hz, 2H), 2.93-3.02 (m, 2H), 3.31 (dt, J=1.8, 12.0 Hz, 2H), 3.64(q, J=7.0 Hz, 2H), 3.72 (s, 6H), 3.90-4.98 (m, 2H), 4.57 (s, 2H), 6.59(dd, J=1.4, 7.0 Hz, 1H), 6.69 (s, 2H), 7.01 (dd, J=7.0, 8.8 Hz, 1H),7.42 (dd, J=1.3, 8.8 Hz, 1H).

Example 24N-Cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(2-methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine

Light green oil

¹H NMR (400 MHz, CDCl₃) δ −0.04-0.02 (m, 2H), 0.32-0.38 (m, 2H),0.78-0.88 (m, 1H), 1.21 (t, J=7.6 Hz, 3H), 1.22-1.32 (m, 2H), 1.52-1.65(m, 1H), 1.70-1.80 (m, 2H), 2.75 (q, J=7.6 Hz, 2H), 2.87 (d, J=6.8 Hz,2H), 2.94 (t, J=6.8 Hz, 2H), 3.03 (d, J=6.8 Hz, 2H), 3.26-3.34 (m, 2H),3.41 (s, 3H), 3.68 (s, 6H), 3.66-3.78 (m, 2H), 3.90-3.96 (m, 2H), 6.55(s, 2H), 6.58 (dd, J=1.2, 6.8 Hz, 1H), 6.99 (dd, J=6.8, 8.8 Hz, 1H),7.42 (dd, J=1.2, 8.8 Hz, 1H).

Example 25N-Cyclopropylmethyl-N-(7-2,6-dimethoxy-4-[(2-morpholinoethoxy)methyl]phenyl-2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-tetrahydro-2H-4-pyranylmethylamine

Yellow crystal

¹H NMR (400 MHz, CDCl₃) δ −0.02-0.01 (m, 2H), 0.33-0.36 (m, 2H),0.80-0.84 (m, 1H), 1.19-1.28 (m, 5H), 1.50-1.60 (m, 1H), 1.70-1.80 (m,2H), 2.52-2.58 (m, 4H), 2.67 (t, J=5.6 Hz, 2H), 2.75 (q, J=7.6 Hz, 2H),2.87 (d, J=6.8 Hz, 2H), 3.04 (d, J=7.2 Hz, 2H), 3.30 (dt, J=2.0, 12.0Hz, 2H), 3.68 (t, J=5.6 Hz, 2H), 3.71 (s, 6H), 3.75 (t, J=4.8 Hz, 4H),3.91-3.95 (m, 2H), 4.60 (s, 2H), 6.58 (dd, J=1.6, 6.8 Hz, 1H), 6.67 (s,2H), 7.00 (dd, J=6.8, 8.8 Hz, 1H), 7.44 (dd, J=1.6, 8.8 Hz, 1H).

Example 26N-Cyclopropylmethyl-N-(7-2,6-dimethoxy-4-[3-(2-morpholinoethoxy)propyl]phenyl-2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-tetrahydro-2H-4-pyranylmethylamine

Yellow oil

¹H NMR (400 MHz, CDCl₃) δ −0.03-0.01 (m, 2H), 0.33-0.37 (m, 2H),0.78-0.88 (m, 1H), 1.17-1.35 (m, 5H), 1.50-1.60 (m, 1H), 1.70-1.78 (m,2H), 1.95-2.02 (m, 2H), 2.45-2.58 (m, 6H), 2.63 (t, J=6.0 Hz, 2H),2.72-2.79 (m, 4H), 2.87 (d, J=6.8 Hz, 2H), 3.04 (d, J=6.8 Hz, 2H), 3.30(dt, J=2.0, 12.0 Hz, 2H), 3.54 (t, J=6.4 Hz, 2H), 3.62 (t, J=6.0 Hz,2H), 3.69-3.75 (m, 8H), 3.92-3.95 (m, 2H), 6.52 (s, 2H), 6.59 (dd,J=1.2, 6.4 Hz, 1H), 7.00 (d, J=6.8, 8.8 Hz, 1H), 7.43 (dd, J=1.6, 7.8Hz, 1H).

Example 27N-Cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(3-methoxypropyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine

Yellow oil

¹H NMR (400 MHz, CDCl₃) δ −0.03-0.01 (m, 2H), 0.33-0.37 (m, 2H),0.81-0.85 (m, 1H), 1.19-1.31 (m, 5H), 1.50-1.60 (m, 1H), 1.72-1.80 (m,2H), 1.94-2.01 (m, 2H), 2.73-2.79 (m, 4H), 2.87 (d, J=6.4 Hz, 2H), 3.04(d, J=6.8 Hz, 2H), 3.30 (dt, J=2.0, 11.6 Hz, 2H), 3.33 (s, 3H), 3.48 (t,J=6.4 Hz, 2H), 3.70 (s, 6H), 3.92-3.95 (m, 2H), 6.53 (s, 2H), 6.59 (dd,J=1.2, 6.8 Hz, 1H), 7.00 (dd, J=6.4, 8.8 Hz, 1H), 7.43 (dd, J=1.2, 8.4Hz, 1H).

Example 28N-7-[4-(Chloromethyl)-2,6-dimethoxyphenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-cyclopropylmethyl-N-tetrahydro-2H-4-pyranylmethylamine

To a solution of(4-3-[(cyclopropylmethyl)(tetrahydro-2H-4-pyranylmethyl)amino]-2-ethylpyrazolo[1,5-a]pyridin-7-yl-3,5-dimethoxyphenyl)methanol(122 mg) in dichloromethane (5 mL) was added triethylamine (0.076 mL),methanesulfonyl chloride (0.023 mL) and 4-(dimethylamino)pyridine (0.5mg) at room temperature, and the reaction mixture was stirred for 2hours. After completion of the reaction, water was added to the reactionmixture, extraction was performed with ethyl acetate and the organicextract was washed with brine and dried over anhydrous magnesiumsulfate, after which the solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography (15 g) andthe title compound (45 mg) was obtained as a yellow amorphous solid fromthe ethyl acetate:n-hexane (1:2) fraction.

¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 2H), 0.33-0.41 (m, 2H),0.79-0.92 (m, 1H), 1.23 (t, J=7.6 Hz, 3H), 1.20-1.36 (m, 2H), 1.53-1.67(m, 1H), 1.72-1.82 (m, 2H), 2.77 (q, J=7.6 Hz, 2H), 2.89 (d, J=6.8 Hz,2H), 3.06 (d, J=7.0 Hz, 2H), 3.32 (dt, J=2.0, 12.0 Hz, 2H), 3.75 (s,6H), 3.90-4.00 (m, 2H), 4.66 (s, 2H), 6.60 (dd, J=1.4, 6.8 Hz, 1H), 6.74(s, 2H), 7.02 (dd, J=6.8, 8.8 Hz, 1H), 7.47 (dd, J=1.5, 8.8 Hz, 1H).

Example 29N-Cyclopropylmethyl-N-2-ethyl-7-[4-(isopropoxymethyl)-2,6-dimethoxyphenyl]pyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine

To a solution of 2-propanol (8 μL) in N,N-dimethylformamide (1.5 mL) wasadded sodium hydride (60% in oil; 4.3 mg) at room temperature, and thereaction mixture was stirred for 15 minutes. A solution ofN-7-[4-(chloromethyl)-2,6-dimethoxyphenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-cyclopropylmethyl-N-tetrahydro-2H-4-pyranylmethylamine(45 mg) in N,N-dimethylformamide (3.5 mL) and sodium iodide (0.5 mg)were added to the obtained reaction mixture, and then the reactionmixture was stirred for 20 minutes at 40° C. and further stirred for 20minutes at 80° C. To the obtained reaction mixture was added ice,extraction was performed with ethyl acetate and the organic extract waswashed with brine and dried over anhydrous magnesium sulfate, afterwhich the solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (10 g) and the titlecompound (9 mg) was obtained as a yellow oil from the ethylacetate:n-hexane (1:2) fraction.

¹H NMR (400 MHz, CDCl₃) δ −0.03-0.04 (m, 2H), 0.32-0.41 (m, 2H),0.79-0.92 (m, 1H), 1.22 (t, J=7.6 Hz, 3H), 1.29 (d, J=6.0 Hz, 6H),1.20-1.36 (m, 2H), 1.53-1.67 (m, 1H), 1.72-1.82 (m, 2H), 2.77 (q, J=7.5Hz, 2H), 2.89 (d, J=6.6 Hz, 2H), 3.06 (d, J=7.0 Hz, 2H), 3.32 (dt,J=2.0, 12.0 Hz, 2H), 3.73 (s, 6H), 3.70-3.84 (m, 1H), 3.90-4.00 (m, 2H),4.59 (s, 2H), 6.59 (dd, J=1.3, 6.8 Hz, 1H), 6.70 (s, 2H), 7.01 (dd,J=6.8, 8.8 Hz, 1H), 7.45 (dd, J=1.5, 8.8 Hz, 1H).

Example 303-(4-3-[(Cyclopropylmethyl)(tetrahydro-2H-4-pyranylmethyl)amino]-2-ethylpyrazolo[1,5-a]pyridin-7-yl-3,5-dimethoxyphenyl)propylmethanesulfonate

To a solution of3-(4-3-[(cyclopropylmethyl)(tetrahydro-2H-4-pyranylmethyl)amino]-2-ethylpyrazolo[1,5-a]pyridin-7-yl-3,5-dimethoxyphenyl)-1-propanol(190 mg) in dichloromethane (20 mL) was added triethylamine (0.062 mL),methanesulfonyl chloride (51 mg) and 4-(dimethylamino)pyridine (0.5 mg)at room temperature, and the reaction mixture was stirred for 2 hours.After completion of the reaction, water was added to the reactionmixture, extraction was performed with ethyl acetate and the organicextract was washed with brine and dried over anhydrous magnesiumsulfate, after which the solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography (15 g) andthe title compound (179 mg) was obtained as a yellow oil from the ethylacetate:n-hexane (1:2) fraction.

¹H NMR (400 MHz, CDCl₃) δ −0.03-0.01 (m, 2H), 0.33-0.37 (m, 2H),0.81-0.85 (m, 1H), 1.19-1.35 (m, 5H), 1.50-1.57 (m, 1H), 1.72-1.77 (m,2H), 1.85-2.00 (m, 2H), 2.70-2.90 (m, 6H), 3.04-3.10 (m, 5H), 3.25-3.35(m, 2H), 3.70 (s, 6H), 4.33 (t, J=6.4 Hz, 2H), 3.91-3.99 (m, 2H), 6.53(s, 2H), 6.59-6.62 (m, 1H), 6.95-7.05 (m, 1H), 7.43-7.48 (m, 1H).

Example 31N-Cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(3-morpholinopropyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine

To a solution of3-(4-3-[(cyclopropylmethyl)(tetrahydro-2H-4-pyranylmethyl)amino]-2-ethylpyrazolo[1,5-a]pyridin-7-yl-3,5-dimethoxyphenyl)propylmethanesulfonate (50 mg) in dichloromethane (10 mL) was added morpholine(60 mg) at room temperature, and the reaction mixture was stirred for 12hours at the same temperature. After completion of the reaction, waterwas added to the reaction mixture, extraction was performed with ethylacetate and the organic extract was washed with brine and dried overanhydrous magnesium sulfate, after which the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (10 g) and the title compound (16 mg) was obtained as ayellow oil from the ethyl acetate fraction.

¹H NMR (400 MHz, CDCl₃) δ −0.02-0.02 (m, 2H), 0.35-0.40 (m, 2H),0.80-0.90 (m, 1H), 1.20-1.35 (m, 5H), 1.55-1.60 (m, 1H), 1.73-1.80 (m,2H), 1.90-1.98 (m, 2H), 2.45-1.52 (m, 6H), 2.70-2.81 (m, 4H), 2.89 (d,J=7.2 Hz, 2H), 3.06 (d, J=7.2 Hz, 2H), 3.32 (br t, J=9.6 Hz, 2H),3.70-3.79 (m, 10H), 3.93-3.97 (m, 2H), 6.54 (s, 2H), 6.61 (dd, J=0.8,6.8 Hz, 1H), 7.06 (dd, J=6.8, 8.8 Hz, 1H), 7.45 (dd, J=1.2, 8.8 Hz, 1H).

Example 32N-Cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(morpholinomethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine

To a solution of4-3-[(cyclopropylmethyl)(tetrahydro-2H-4-pyranylmethyl)amino]-2-ethylpyrazolo[1,5-a]pyridin-7-yl-3,5-dimethoxybenzaldehyde(15 mg) in acetic acid (0.5 mL) and tetrahydrofuran (0.5 mL) was addedmorpholine (3.2 mg) while stirring at room temperature, and then sodiumtriacetoxyborohydride (8 mg) was added and the reaction mixture wasstirred for 2 hours. Water was added to the obtained reaction mixtureand extraction was performed with ethyl acetate. The obtained organicextract was dried over anhydrous magnesium sulfate and filtered, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography and the title compound (8.5mg) was obtained as a yellow oil from the ethyl acetate:n-hexane (2:1)fraction.

¹H NMR (400 MHz, CDCl₃) δ −0.04-0.01 (m, 2H), 0.32-0.38 (m, 2H),0.78-0.88 (m, 1H), 1.18-1.32 (m, 5H), 1.50-1.62 (m, 1H), 1.72-1.78 (m,2H), 2.48-2.58 (m, 4H), 2.76 (q, J=8.0 Hz, 2H), 2.87 (d, J=6.8 Hz, 2H),3.04 (d, J=7.2 Hz, 2H), 3.26-3.34 (m, 2H), 3.54 (s, 2H), 3.71 (s, 6H),3.75-3.78 (m, 4H), 3.91-3.95 (m, 2H), 6.59 (br d, J=6.8 Hz, 1H), 6.69(s, 2H), 7.00 (dd, J=6.8, 8.8 Hz, 1H), 7.44 (br d, J=8.8 Hz, 1H).

Similarly to Example 32, the compounds of Example 33 and 34 weresynthesized.

Example 33N3-Cyclopropylmethyl-N3-tetrahydro-2H-4-pyranylmethyl-7-4-[(dimethylamino)methyl]-2,6-dimethoxyphenyl-2-ethylpyrazolo[1,5-a]pyridin-3-amine

Yellow oil

¹H NMR (400 MHz, CDCl₃) δ −0.03-0.01 (m, 2H), 0.32-0.37 (m, 2H),0.78-0.90 (m, 1H), 1.18-1.32 (m, 5H), 1.50-1.62 (m, 1H), 1.70-1.78 (m,2H), 2.34 (br s, 6H), 2.76 (q, J=7.6 Hz, 2H), 2.87 (d, J=6.8 Hz, 2H),3.04 (d, J=6.8 Hz, 2H), 3.25-3.35 (m, 2H), 3.45-3.52 (m, 2H), 3.71 (s,6H), 3.90-3.95 (m, 2H), 6.60 (dd, J=1.2, 6.8 Hz, 1H), 6.67 (s, 2H), 7.00(dd, J=7.2, 8.4 Hz, 1H), 7.44 (dd, J=1.2, 8.8 Hz, 1H).

Example 34N-Cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(tetrahydro-1H-1-pyrrolylmethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine

Yellow oil

¹H NMR (400 MHz, CDCl₃) δ −0.02-0.00 (m, 2H), 0.30-0.40 (m, 2H),0.80-0.88 (m, 1H), 1.19-1.32 (m, 5H), 1.50-1.64 (m, 1H), 1.72-1.78 (m,2H), 1.80-1.90 (m, 4H), 2.56-2.68 (m, 4H), 2.76 (q, J=7.6 Hz, 2H), 2.87(d, J=6.8 Hz, 2H), 3.04 (d, J=6.8 Hz, 2H), 3.26-3.34 (m, 2H), 3.67 (brs, 2H), 3.71 (s, 6H), 3.92-3.95 (m, 2H), 6.59 (dd, J=0.8, 6.8 Hz, 1H),6.69 (s, 2H), 6.98-7.02 (m, 1H), 7.44 (br d, J=8.8 Hz, 1H).

Example 35 tert-ButylN-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-methylpyrazolo[1,5-a]pyridin-3-ylcarbamate

To a solution of tert-butylN-(7-bromo-2-methylpyrazolo[1,5-a]pyridin-3-yl)carbamate (300 mg)dissolved in a mixture of 1,2-dimethoxyethane (10 mL) and water (5 mL)was added 2,6-dimethoxy-4-methoxymethylphenylboric acid (353 mg),tetrakis(triphenylphosphine)palladium(0) (159 mg) and barium hydroxideoctahydrate (435 mg), and the reaction mixture was heated and stirredfor 6 hours at 80° C. under a nitrogen stream. Water was added to theobtained reaction mixture, extraction was performed with ethyl acetate,the organic extract was washed with brine, dried over anhydrousmagnesium sulfate and filtered, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography and the title compound (176 mg) was obtained as a lightbrown oil from the n-hexane:ethyl acetate (1:1) fraction.

¹H NMR (400 MHz, CDCl₃) δ 1.54 (br s, 9H), 3.32 (s, 3H), 3.47 (s, 3H),3.69 (s, 6H), 4.51 (s, 2H), 5.86-5.92 (m, 1H), 6.56-6.61 (m, 1H), 6.65(s, 2H), 7.11 (dd, J=6.8, 8.8 Hz, 1H), 7.34 (dd, J=1.2, 8.8 Hz, 1H).

Example 36N-Cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-methylpyrazolo[1,5-a]pyridin-3-ylamine

To a solution of tert-butylN-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-methylpyrazolo[1,5-a]pyridin-3-ylcarbamate(175 mg) dissolved in N,N-dimethylformamide (4 mL) was added sodiumhydride (60% in oil; 25 mg) and (bromomethyl)cyclopropane (0.047 mL),and the reaction mixture was stirred for 1 hour at 40° C. Water wasadded to the obtained reaction mixture, extraction was performed withethyl acetate, and the organic extract was washed with brine. Theobtained organic extract was dried over anhydrous magnesium sulfate andfiltered, and the solvent was evaporated under reduced pressure toafford a crude product of tert-butylN-cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-methylpyrazolo[1,5-a]pyridin-3-ylcarbamate.

The obtained crude product of tert-butylN-cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-methylpyrazolo[1,5-a]pyridin-3-ylcarbamatewas dissolved in ethyl acetate (5 mL) without purification, 4Nhydrochloric acid (ethyl acetate solution; 10 mL) was added thereto atroom temperature, and the reaction mixture was stirred for 1 hour at 40°C. After neutralizing the reaction mixture with a 5N aqueous sodiumhydroxide solution while cooling with ice, extraction was performed withethyl acetate, the organic extract was washed with brine, dried overanhydrous magnesium sulfate and filtered, the solvent was evaporatedunder reduced pressure, the residue was purified by silica gel columnchromatography and the title compound (100 mg) was obtained as a yellowoil from the n-hexane:ethyl acetate (1:2) fraction.

¹H NMR (400 MHz, CDCl₃) δ 0.15-0.20 (m, 2H), 0.48-0.54 (m, 2H),1.02-1.10 (m, 1H), 2.35 (s, 3H), 2.88 (d, J=6.8 Hz, 2H), 3.47 (s, 3H),3.70 (s, 6H), 4.51 (s, 2H), 6.63 (dd, J=1.2, 6.8 Hz, 1H), 6.65 (s, 2H),6.99 (dd, J=6.8, 8.8 Hz, 1H), 7.36-7.40 (m, 1H).

Example 37N-Cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-methylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine

To a solution ofN-cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-methylpyrazolo[1,5-a]pyridin-3-ylamine(60 mg) dissolved in tetrahydrofuran (3 mL) was addedtetrahydropyran-4-carbaldehyde (36 mg) and sodium triacetoxyborohydride(67 mg), and the reaction mixture was stirred for 1 hour at roomtemperature. Water and then saturated aqueous sodium bicarbonate wereadded to the obtained reaction mixture, extraction was performed withethyl acetate, the organic extract was washed with brine, dried overanhydrous magnesium sulfate and filtered, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography, and the crystals obtained from the n-hexane:ethylacetate (1:1) fraction were filtered, washed with n-hexane and thendried to afford the title compound (63 mg) as light yellow crystals.

¹H NMR (400 MHz, CDCl₃) δ −0.05-0.02 (m, 2H), 0.31-0.36 (m, 2H),0.78-0.88 (m, 1H), 1.20-1.32 (m, 2H), 1.54-1.64 (m, 1H), 1.72-1.78 (m,2H), 2.34 (s, 3H), 2.85 (d, J=7.2 Hz, 2H), 3.03 (d, J=7.2 Hz, 2H),3.26-3.34 (m, 2H), 3.47 (s, 3H), 3.71 (s, 6H), 3.90-3.96 (m, 2H), 4.51(s, 2H), 6.53 (dd, J=1.2, 6.8 Hz, 1H), 6.66 (s, 2H), 7.00 (dd, J=6.8,8.8 Hz, 1H), 7.42 (dd, J=1.2, 8.8 Hz, 1H).

Example 38N-Cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-methylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-3-furanylmethylamine

To a solution ofN-cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-methylpyrazolo[1,5-a]pyridin-3-ylamine(40 mg) dissolved in tetrahydrofuran (3 mL) was addedtetrahydrofuran-3-carbaldehyde (50% aqueous solution; 0.064 mL), 3 Maqueous sulfuric acid (0.105 mL) and sodium borohydride (8 mg) whilecooling with ice, and the reaction mixture was stirred for 1 hour. Waterand then saturated aqueous sodium bicarbonate were added to the obtainedreaction mixture, extraction was performed with ethyl acetate, and theorganic extract was washed with brine. The obtained organic extract wasdried over anhydrous magnesium sulfate and filtered, the solvent wasevaporated under reduced pressure, the residue was purified by silicagel column chromatography and the title compound (30 mg) was obtained aslight yellow crystals from the n-hexane:ethyl acetate (1:1) fraction.

¹H NMR (400 MHz, CDCl₃) δ −0.03-0.03 (m, 2H), 0.33-0.38 (m, 2H),0.80-0.90 (m, 1H), 1.54-1.68 (m, 1H), 1.85-1.95 (m, 1H), 2.20-2.29 (m,1H), 2.33 (s, 3H), 2.87-2.90 (m, 2H), 3.06 (dd, J=8.8, 12.0 Hz, 1H),3.22 (dd, J=6.4, 12.0 Hz, 1H), 3.47 (s, 3H), 3.59-3.70 (m, 2H), 3.71 (s,6H), 3.72-3.88 (m, 2H), 4.51 (s, 2H), 6.54 (dd, J=1.2, 6.8 Hz, 1H), 6.66(s, 2H), 7.01 (dd, J=6.8, 8.8 Hz, 1H), 7.41 (dd, J=1.2, 8.8 Hz, 1H).

Similarly to Example 20, the compounds of Example 39 and 40 wereobtained.

Example 39(4-3-[(Cyclopropylamine)(tetrahydro-2H-4-pyranylmethyl)amino]-2-methylpyrazolo[1,5-a]pyridin-7-yl-3,5-dimethoxyphenyl)methanol

Yellow oil

¹H NMR (400 MHz, CDCl₃) δ −0.04-0.06 (m, 2H), 0.34-0.42 (m, 2H),0.80-0.94 (m, 1H), 1.23-1.38 (m, 2H), 1.54-1.72 (m, 1H), 1.74-1.84 (m,2H), 2.38 (s, 3H), 2.47 (br s, 1H), 2.89 (d, J=6.8 Hz, 2H), 3.07 (d,J=7.0 Hz, 2H), 3.34 (dt, J=2.0, 12.0 Hz, 2H), 3.74 (s, 6H), 3.90-4.02(m, 2H), 4.71 (s, 2H), 6.57 (dd, J=1.4, 6.8 Hz, 1H), 6.71 (s, 2H), 7.05(dd, J=6.8, 8.8 Hz, 1H), 7.52-7.60 (m, 1H).

Example 40N-Cyclopropylamine-N-7-[4-(ethoxymethyl)-2,6-dimethoxyphenyl]-2-methylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine

Yellow oil

¹H NMR (400 MHz, CDCl₃) δ −0.03-0.05 (m, 2H), 0.32-0.42 (m, 2H),0.80-0.94 (m, 1H), 1.34 (t, J=7.2 Hz, 3H), 1.22-1.38 (m, 2H), 1.54-1.70(m, 1H), 1.74-1.84 (m, 2H), 2.38 (s, 3H), 2.89 (d, J=6.8 Hz, 2H), 3.07(d, J=7.2 Hz, 2H), 3.34 (dt, J=1.6, 12.0 Hz, 2H), 3.66 (q, J=7.2 Hz,2H), 3.75 (s, 6H), 3.92-4.02 (m, 2H), 4.59 (s, 2H), 6.57 (dd, J=1.4, 6.8Hz, 1H), 6.72 (s, 2H), 7.04 (dd, J=6.8, 8.8 Hz, 1H), 7.45 (dd, J=1.4,8.8 Hz, 1H).

Example 41 tert-ButylN-[7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-(methoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate

To a solution of tert-butylN-[7-bromo-2-(methoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate (300mg) dissolved in 1,2-dimethoxyethane (10 mL) and water (5 mL) was added2,6-dimethoxy-4-methoxymethylphenylboric acid (323 mg),tetrakis(triphenylphosphine)palladium(0) (146 mg) and barium hydroxideoctahydrate (398 mg), and the reaction mixture was heated and stirredfor 2 hours at 80° C. under a nitrogen stream. Water was added to theobtained reaction mixture, the reaction mixture was extracted with ethylacetate, and the organic extract was washed with brine. The obtainedorganic extract was dried over anhydrous magnesium sulfate and filtered,and the solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography and the title compound (245mg) was obtained as a light yellow amorphous solid from then-hexane:ethyl acetate (1:1) fraction.

¹H NMR (400 MHz, CDCl₃) δ 1.55 (br s, 9H), 3.32 (s, 3H), 3.76 (s, 3H),3.68 (s, 6H), 4.51 (s, 2H), 4.62 (s, 2H), 6.37-6.46 (m, 1H), 6.65 (s,2H), 7.13 (dd, J=6.8, 8.8 Hz, 1H), 7.50-7.58 (m, 1H).

Example 42N-Cyclopropylmethyl-N-[7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-(methoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]amine

To a solution of tert-butylN-[7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-(methoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate(170 mg) dissolved in N,N-dimethylformamide (4 mL) was added sodiumhydride (60% in oil; 22 mg) and (bromomethyl)cyclopropane (0.043 mL),and the reaction mixture was stirred for 30 minutes at 40° C. Water wasadded to the obtained reaction mixture, extraction was performed withethyl acetate and the organic extract was washed with brine. Theobtained organic extract was dried over anhydrous magnesium sulfate andfiltered, and the solvent was evaporated under reduced pressure toafford a crude product of tert-butylN-cyclopropylmethyl-N-[7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-(methoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate.

The obtained tert-butylN-cyclopropylmethyl-N-[7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-(methoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]carbamatewas dissolved in ethyl acetate (5 mL) without purification, and then 4Nhydrochloric acid (ethyl acetate solution; 10 mL) was added thereto andthe reaction mixture was stirred for 30 minutes at 40° C. The reactionmixture was neutralized with a 5N aqueous sodium hydroxide solutionwhile cooling with ice, and then the reaction mixture was extracted withethyl acetate and the organic extract was washed with water and brine.The organic extract was dried over anhydrous magnesium sulfate andfiltered, the solvent was evaporated under reduced pressure, the residuewas purified by silica gel column chromatography and the title compound(95 mg) was obtained as a yellow oil from the n-hexane:ethyl:acetate(2:3) fraction.

¹H NMR (400 MHz, CDCl₃) δ 0.15-0.20 (m, 2H), 0.48-0.54 (m, 2H),1.02-1.10 (m, 1H), 1.20-1.32 (m, 2H), 2.35 (s, 3H), 2.88 (d, J=6.8 Hz,2H), 3.47 (s, 3H), 3.70 (s, 6H), 4.51 (s, 2H), 6.63 (dd, J=1.2, 6.8 Hz,1H), 6.65 (s, 2H), 6.99 (dd, J=6.8, 8.8 Hz, 1H), 7.36-7.40 (m, 1H).

Example 43N-Cyclopropylmethyl-N-[7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-(methoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

To a solution ofN-cyclopropylmethyl-N-[7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-(methoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]amine(80 mg) dissolved in tetrahydrofuran (2 mL) was addedtetrahydropyran-4-carbaldehyde (44 mg) and sodium triacetoxyborohydride(82 mg), and the reaction mixture was stirred for 30 minutes at roomtemperature. Water and saturated aqueous sodium bicarbonate were addedto the reaction mixture, extraction was performed with ethyl acetate andthe organic extract was washed with brine. The organic extract was driedover anhydrous magnesium sulfate and filtered, the solvent wasevaporated under reduced pressure, the residue was purified by silicagel column chromatography and the title compound (63 mg) was obtained asa yellow oil from the n-hexane:ethyl acetate (1:2) fraction.

¹H NMR (400 MHz, CDCl₃) δ −0.01-0.01 (m, 2H), 0.33-0.37 (m, 2H),0.78-0.88 (m, 1H), 1.20-1.32 (m, 2H), 1.52-1.65 (m, 1H), 1.72-1.78 (m,2H), 2.87 (d, J=6.8 Hz, 2H), 3.05 (d, J=6.8 Hz, 2H), 3.26-3.33 (m, 2H),3.29 (s, 3H), 3.48 (s, 3H), 3.70 (s, 6H), 3.89-3.95 (m, 2H), 4.51 (s,2H), 4.56 (s, 2H), 6.63 (dd, J=1.2, 6.8 Hz, 1H), 6.65 (s, 2H), 7.03 (dd,J=6.8, 8.8 Hz, 1H), 7.51 (dd, J=1.2, 8.8 Hz, 1H).

Example 44N-Cyclopropylmethyl-N-[7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-(methoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethylamine

To a solution ofN-cyclopropylmethyl-N-[7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-(methoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]amine(15 mg) dissolved in tetrahydrofuran (1 mL) was addedtetrahydrofuran-3-carbaldehyde (50% aqueous solution; 0.022 mL), a 3Maqueous sulfuric acid solution (0.036 mL) and sodium borohydride (2.8mg) while cooling with ice and the reaction mixture was stirred for 1hour at the same temperature. Water and then saturated aqueous sodiumbicarbonate were added to the obtained reaction mixture, extraction wasperformed with ethyl acetate, the organic extract was washed with brine,dried over anhydrous magnesium sulfate and filtered, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography and the title compound (4.8 mg) was obtainedas light yellow crystals from the n-hexane:ethyl acetate (1:2) fraction.

¹H NMR (400 MHz, CDCl₃) δ 0.00-0.06 (m, 2H), 0.32-0.40 (m, 2H),0.80-0.90 (m, 1H), 1.55-1.68 (m, 1H), 1.86-1.95 (m, 1H), 2.21-2.32 (m,1H), 2.88-2.92 (m, 2H), 3.08 (dd, J=8.8, 12.0 Hz, 1H), 3.23 (dd, J=6.8,12.0 Hz, 1H), 3.30 (s, 3H), 3.48 (s, 3H), 3.60-3.68 (m, 2H), 3.69 (s,6H), 3.72-3.84 (m, 2H), 4.51 (s, 2H), 4.55 (s, 2H), 6.54 (dd, J=1.2, 6.8Hz, 1H), 6.66 (s, 2H), 7.01 (dd, J=6.8, 8.8 Hz, 1H), 7.41 (dd, J=1.2,8.8 Hz, 1H).

Similarly to Example 20, the compound of Example 45 and 46 wereobtained.

Example 454-[3-[(Cyclopropylamine)(tetrahydro-2H-4-pyranylmethyl)amino]-2-(methoxymethyl)pyrazolo[1,5-a]pyridin-7-yl]-3,5-dimethoxyphenylmethanol

Yellow oil

¹H NMR (400 MHz, CDCl₃) δ −0.04-0.04 (m, 2H), 0.30-0.40 (m, 2H),0.78-0.92 (m, 1H), 1.20-1.34 (m, 2H), 1.53-1.70 (m, 1H), 1.71-1.80 (m,2H), 2.20 (br s, 1H), 2.88 (d, J=6.8 Hz, 2H), 3.05 (d, J=7.2 Hz, 2H),3.29 (s, 3H), 3.24-3.38 (m, 2H), 3.70 (s, 6H), 3.88-3.98 (m, 2H), 4.57(s, 2H), 4.71 (s, 2H), 6.63 (dd, J=1.4, 6.8 Hz, 1H), 6.68 (s, 2H), 7.05(dd, J=6.8, 8.8 Hz, 1H), 7.49-7.57 (m, 1H).

Example 46N-Cyclopropylamine-N-[7-[4-(ethoxymethyl)-2,6-dimethoxyphenyl]-2-(methoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

Yellow oil

¹H NMR (400 MHz, CDCl₃) δ −0.04-0.04 (m, 2H), 0.30-0.40 (m, 2H),0.78-0.92 (m, 1H), 1.31 (t, J=6.8 Hz, 3H), 1.20-1.36 (m, 2H), 1.54-1.68(m, 1H), 1.70-1.81 (m, 2H), 2.89 (d, J=6.8 Hz, 2H), 3.06 (d, J=6.8 Hz,2H), 3.30 (s, 3H), 3.26-3.36 (m, 2H), 3.64 (q, J=6.8 Hz, 2H), 3.71 (s,6H), 3.89-3.98 (m, 2H), 4.56 (s, 2H), 4.57 (s, 2H), 6.64 (dd, J=1.6, 6.8Hz, 1H), 6.68 (s, 2H), 7.05 (dd, J=6.8, 8.8 Hz, 1H), 7.52 (dd, J=1.6,8.8 Hz, 1H).

Example 47N-Cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-methoxypyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine

To a solution ofN-(7-bromo-2-methoxypyrazolo[1,5-a]pyridin-3-yl)-N-cyclopropylmethyl-N-tetrahydro-2H-4-pyranylmethylamine(48 mg) dissolved in a mixture of 1,2-dimethoxyethane (2 mL) and water(1 mL) was added 2,6-dimethoxy-4-(methoxymethyl)phenylboric acid (36mg), tetrakis(triphenylphosphine)palladium(0) (28 mg) and bariumhydroxide octahydrate (58 mg), and the reaction mixture was heated andstirred for 2 hours at 85° C. Water and ethyl acetate were added to theobtained reaction mixture, the reaction mixture was filtered throughcelite to remove insoluble residue, and then the filtrate was extractedwith ethyl acetate. The obtained organic extract was washed with brine,dried over anhydrous magnesium sulfate and filtered, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography and the title compound (40 mg) wasobtained as light yellow crystals from the n-hexane:ethyl:acetate (2:1)fraction.

¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 2H), 0.30-0.36 (m, 2H),0.80-0.92 (m, 1H), 1.24-1.36 (m, 2H), 1.52-1.64 (m, 1H), 1.74-1.82 (m,2H), 2.84 (d, J=6.8 Hz, 2H), 2.97 (d, J=6.8 Hz, 2H), 3.32 (td, J=2.0,11.6 Hz, 2H), 3.51 (s, 3H), 3.76 (s, 6H), 3.87 (s, 3H), 3.90-3.98 (m,2H), 4.55 (s, 2H), 6.51 (dd, J=1.6, 6.8 Hz, 1H), 6.69 (s, 2H), 7.04 (dd,J=7.2, 8.8 Hz, 1H), 7.33 (dd, J=1.6, 8.8 Hz, 1H).

Similarly to Example 47, the compounds of Example 48 to 51 weresynthesized.

Example 48N-Cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(1-methoxyethyl)phenyl]-2-methoxypyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine

Light yellow crystals

¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 2H), 0.30-0.38 (m, 2H),0.80-0.92 (m, 1H), 1.22-1.34 (m, 2H), 1.55 (d, J=1.6 Hz, 3H), 1.56-1.68(m, 1H), 1.72-1.82 (m, 2H), 2.84 (d, J=6.8 Hz, 2H), 2.97 (d, J=7.2 Hz,2H), 3.26-3.34 (m, 2H), 3.37 (s, 3H), 3.77 (s, 6H), 3.89 (s, 3H),3.90-3.98 (m, 2H), 4.37 (q, J=6.4 Hz, 1H), 6.53 (dd, J=1.2, 7.2 Hz, 1H),6.66 (d, J=3.2 Hz, 2H), 7.04 (dd, J=7.2, 8.8 Hz, 1H), 7.33 (dd, J=1.6,8.8 Hz, 1H).

Example 49(4-3-[(Cyclopropylmethyl)(tetrahydro-2H-4-pyranylmethyl)amino]-2-methoxypyrazolo[1,5-a]pyridin-7-yl-3,5-dimethoxyphenyl)methanol

Yellow amorphous solid

¹H NMR (400 MHz, CDCl₃) δ −0.02-0.06 (m, 2H), 0.30-0.38 (m, 2H),0.80-0.93 (m, 1H), 1.23-1.38 (m, 2H), 1.53-1.67 (m, 1H), 1.74-1.88 (m,2H), 2.84 (d, J=6.6 Hz, 2H), 2.98 (d, J=7.0 Hz, 2H), 3.33 (dt, J=1.7,12.0 Hz, 2H), 3.77 (s, 6H), 3.88 (s, 3H), 3.91-4.00 (m, 2H), 4.81 (br d,J=4.6 Hz, 2H), 6.50-6.55 (m, 1H), 6.74 (s, 2H), 7.02-7.09 (m, 1H),7.32-7.38 (m, 1H).

Example 50N-Cyclopropylmethyl-N-7-[4-(ethoxymethyl)-2,6-dimethoxyphenyl]-2-methoxypyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine

Yellow oil

¹H NMR (400 MHz, CDCl₃) δ −0.02-0.07 (m, 2H), 0.30-0.39 (m, 2H),0.82-0.95 (m, 1H), 1.36 (t, J=7.0 Hz, 3H), 1.25-1.39 (m, 2H), 1.55-1.68(m, 1H), 1.75-1.84 (m, 2H), 2.85 (d, J=6.8 Hz, 2H), 2.99 (d, J=7.0 Hz,2H), 3.34 (dt, J=1.8, 12.0 Hz, 2H), 3.69 (q, J=7.0 Hz, 2H), 3.78 (s,6H), 3.89 (s, 3H), 3.92-4.00 (m, 2H), 4.62 (s, 2H), 6.52 (dd, J=1.4, 6.9Hz, 1H), 6.72 (s, 2H), 7.06 (dd, J=6.9, 8.9 Hz, 1H), 7.35 (dd, J=1.4,8.9 Hz, 1H).

Example 51N-Cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-methoxypyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-3-furanylmethylamine

Light yellow crystals

¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 2H), 0.28-0.34 (m, 2H),0.78-0.86 (m, 1H), 1.60-1.68 (m, 1H), 1.84-1.94 (m, 1H), 2.20-2.30 (m,1H), 2.83 (d, J=6.8 Hz, 2H), 2.92-3.00 (m, 1H), 3.10-3.14 (m, 1H), 3.48(s, 3H), 3.52-3.68 (m, 2H), 3.73 (s, 6H), 3.74-3.82 (m, 2H), 3.84 (s,3H), 4.52 (s, 2H), 6.48 (dd, J=1.2, 7.2 Hz, 1H), 6.65 (s, 2H), 7.02 (dd,J=7.2, 8.8 Hz, 1H), 7.29 (dd, J=1.2, 8.8 Hz, 1H).

Example 52 tert-ButylN-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-methoxypyrazolo[1,5-a]pyridin-3-ylcarbamate

To a solution of tert-butylN-(7-bromo-2-methoxypyrazolo[1,5-a]pyridin-3-yl)carbamate (200 mg)dissolved in 1,2-dimethoxyethane (12 mL) and water (6 mL) was added2,6-dimethoxy-4-(methoxymethyl)phenylboric acid (197 mg),tetrakis(triphenylphosphine)palladium(0) (101 mg) and barium hydroxideoctahydrate (274 mg), and the reaction mixture was heated and stirredfor 4 hours at 80° C. under a nitrogen stream. Ethyl acetate was addedto the obtained reaction mixture, and after filtering out the insolubleresidue, the reaction mixture was extracted with ethyl acetate, theorganic extract was washed with brine, dried over anhydrous magnesiumsulfate and filtered, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatographyand the title compound (150 mg) was obtained as a light yellow oil fromthe n-hexane:ethyl acetate (1:1) fraction.

¹H NMR (400 MHz, CDCl₃) δ 1.52 (br s, 9H), 3.48 (s, 3H), 3.70 (s, 6H),3.87 (s, 3H), 4.51 (s, 2H), 5.82 (br s, 1H), 6.53 (d, J=6.8 Hz, 1H),6.64 (s, 2H), 7.10 (dd, J=6.8, 8.8 Hz, 1H), 7.27 (d, J=8.8 Hz, 1H).

Example 53N-Cyclobutylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-methoxypyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine

To a solution of tert-butylN-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-methoxypyrazolo[1,5-a]pyridin-3-ylcarbamate(75 mg) dissolved in N,N-dimethylformamide (0.6 mL) was added sodiumhydride (60% in oil; 10 mg) and (bromomethyl)cyclobutane (0.022 mL), andthe reaction mixture was stirred for 1 hour at room temperature. Waterwas added to the obtained reaction mixture, extraction was performedwith ethyl acetate and the organic extract was washed with brine. Theorganic extract was dried over anhydrous magnesium sulfate and filtered,and the solvent was evaporated under reduced pressure to afford a crudeproduct of tert-butylN-cyclobutylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-methoxypyrazolo[1,5-a]pyridin-3-ylcarbamate.

To the obtained crude product of tert-butylN-cyclobutylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-methoxypyrazolo[1,5-a]pyridin-3-ylcarbamatewithout further purification was added 4N hydrochloric acid (ethylacetate solution; 1 mL), and the reaction mixture was stirred for 1 hourat 40° C. The obtained reaction mixture was neutralized with a 2Naqueous sodium hydroxide solution while cooling with ice, and thenextraction was performed with ethyl acetate and the organic extract waswashed with brine. The organic extract was dried over anhydrousmagnesium sulfate and filtered, the residue was purified by silica gelcolumn chromatography, andN-cyclobutylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-methoxypyrazolo[1,5-a]pyridin-3-ylamine(51 mg) was obtained as a yellow oil from the n-hexane:ethyl acetate(1:1) fraction.

To a solution of the obtainedN-cyclobutylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-methoxypyrazolo[1,5-a]pyridin-3-ylaminedissolved in tetrahydrofuran (0.6 mL) was addedtetrahydropyran-4-carbaldehyde (34 mg) and sodium triacetoxyborohydride(38 mg), and the reaction mixture was stirred for 2 hours at roomtemperature. Saturated aqueous sodium bicarbonate was added to theobtained reaction mixture, extraction was performed with ethyl acetateand the organic extract was washed with brine. The organic extract wasdried over anhydrous magnesium sulfate and filtered, the solvent wasevaporated under reduced pressure, the residue was purified by silicagel column chromatography and the title compound (52 mg) was obtained asa yellow oil from the n-hexane:ethyl acetate (3:2) fraction.

¹H NMR (400 MHz, CDCl₃) δ 1.17-1.30 (m, 2H), 1.48-1.63 (m, 3H),1.69-1.89 (m, 6H), 2.26-2.39 (m, 1H), 2.82-2.87 (m, 2H), 2.93-2.98 (m,2H), 3.24-3.34 (m, 2H), 3.49 (s, 3H), 3.73 (s, 6H), 3.85 (s, 3H),3.88-3.96 (m, 2H), 4.53 (s, 2H), 6.48 (dd, J=1.3, 6.8 Hz, 1H), 6.66 (s,2H), 7.02 (dd, J=6.8, 8.8 Hz, 1H), 7.24 (dd, J=1.3, 8.8 Hz, 1H).

Similarly to Example 53, the compounds of Example 54 to 56 weresynthesized.

Example 54N-Butyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-methoxypyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine

Yellow oil

¹H NMR (400 MHz, CDCl₃) δ 0.81-0.89 (m, 3H), 1.18-1.40 (m, 6H),1.48-1.60 (m, 1H), 1.70-1.78 (m, 2H), 2.83-2.98 (m, 4H), 3.24-3.34 (m,2H), 3.49 (s, 3H), 3.74 (s, 6H), 3.85 (s, 3H), 3.88-3.97 (m, 2H), 4.53(s, 2H), 6.49 (dd, J=1.3, 6.8 Hz, 1H), 6.67 (s, 2H), 7.02 (dd, J=6.8,8.8 Hz, 1H), 7.26 (dd, J=1.3, 8.8 Hz, 1H).

Example 55N-7-[2,6-Dimethoxy-4-(methoxymethyl)phenyl]-2-methoxypyrazolo[1,5-a]pyridin-3-yl-N-propyl-N-tetrahydro-2H-4-pyranylmethylamine

Light yellow amorphous solid

¹H NMR (400 MHz, CDCl₃) δ 0.87 (t, J=7.6 Hz, 3H), 1.20-1.31 (m, 2H),1.33-1.42 (m, 2H), 1.48-1.62 (m, 1H), 1.71-1.78 (m, 2H), 2.87 (d, J=7.2Hz, 2H), 2.90 (d, J=7.2 Hz, 2H), 3.25-3.34 (m, 2H), 3.48 (s, 3H), 3.73(s, 6H), 3.84 (s, 3H), 3.88-3.95 (m, 2H), 4.52 (s, 2H), 6.47 (dd, J=1.2,6.8 Hz, 1H), 6.66 (s, 2H), 7.00 (dd, J=6.8, 8.8 Hz, 1H), 7.25 (dd,J=1.2, 8.8 Hz, 1H).

Example 56N-7-[2,6-Dimethoxy-4-(methoxymethyl)phenyl]-2-methoxypyrazolo[1,5-a]pyridin-3-yl-N-isobutyl-N-tetrahydro-2H-4-pyranylmethylamine

Light yellow amorphous solid

¹H NMR (400 MHz, CDCl₃) δ 0.90 (d, J=6.4 Hz, 6H), 1.19-1.30 (m, 2H),1.48-1.60 (m, 2H), 1.74-1.81 (m, 2H), 2.72 (d, J=7.2 Hz, 2H), 2.82 (d,J=7.2 Hz, 2H), 3.26-3.34 (m, 2H), 3.48 (s, 3H), 3.73 (s, 6H), 3.84 (s,3H), 3.89-3.95 (m, 2H), 4.52 (s, 2H), 6.47 (dd, J=1.2, 6.8 Hz, 1H), 6.66(s, 2H), 7.00 (dd, J=6.8, 8.8 Hz, 1H), 7.26 (dd, J=1.2, 8.8 Hz, 1H).

Similarly to Example 18, the compound of Example 57 was synthesized.

Example 571-(4-3-[(Cyclopropylmethyl)(tetrahydro-2H-4-pyranylmethyl)amino]-2-methoxypyrazolo[1,5-a]pyridin-7-yl-3,5-dimethoxyphenyl)-1-ethanol

Light yellow amorphous solid

¹H NMR (400 MHz, CDCl₃) δ −0.06-0.01 (m, 2H), 0.27-0.34 (m, 2H),0.78-0.89 (m, 1H), 1.20-1.34 (m, 2H), 1.49-1.63 (m, 4H), 1.71-1.80 (m,2H), 2.78-2.84 (m, 2H), 2.91-2.99 (m, 2H), 3.24-3.35 (m, 2H), 3.74 (s,3H), 3.75 (s, 3H), 3.86 (s, 3H), 3.88-3.97 (m, 2H), 4.93-5.01 (m, 1H),6.49 (dd, J=1.3, 6.8 Hz, 1H), 6.68 (s, 1H), 6.74 (s, 1H), 7.02 (dd,J=6.8, 8.8 Hz, 1H), 7.31 (dd, J=1.3, 8.8 Hz, 1H).

Similarly to Example 47, the compound of Example 58 was synthesized.

Example 58N-Cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethoxypyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine

Yellow oil

¹H NMR (400 MHz, CDCl₃) δ −0.04-0.02 (m, 2H), 0.28-0.31 (m, 2H),0.78-0.88 (m, 1H), 1.20-1.32 (m, 5H), 1.50-1.60 (m, 1H), 1.70-1.78 (m,2H), 2.81 (d, J=6.4 Hz, 2H), 2.95 (d, J=6.8 Hz, 2H), 3.29 (dt, J=2.0,11.6 Hz, 2H), 3.48 (s, 3H), 3.72 (s, 6H), 3.89-3.93 (m, 2H), 4.21 (q,J=7.2 Hz, 2H), 4.52 (s, 2H), 6.47 (dd, J=1.2, 6.8 Hz, 1H), 6.66 (s, 2H),7.00 (dd, J=7.2, 8.8 Hz, 1H), 7.30 (dd, J=1.2, 8.8 Hz, 1H).

Example 59N-Cyclopropylmethyl-N-[7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

To a solution ofN-cyclopropylmethyl-N-[7-iodo-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine(50 mg) dissolved in a mixture of 1,2-dimethoxyethane (2 mL) and water(1 mL) was added 2,6-dimethoxy-4-(methoxymethyl)phenylboric acid (50mg), tetrakis(triphenylphosphine)palladium(0) (40 mg) and bariumhydroxide octahydrate (56 mg), and the reaction mixture was heated andstirred for 3 hours at 80° C. Water and ethyl acetate were added to theobtained reaction mixture, insoluble residue was filtered out withcelite, and the filtrate was extracted with ethyl acetate. The organicextracts were combined and washed with brine, dried over anhydrousmagnesium sulfate and filtered, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography and then by column chromatography using NH Silica (FujiSilysia) to afford the title compound (36 mg) as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 2H), 0.30-0.38 (m, 2H),0.82-0.92 (m, 1H), 1.22-1.34 (m, 2H), 1.52-1.64 (m, 1H), 1.76-1.82 (m,2H), 2.44 (s, 3H), 2.90 (d, J=6.8 Hz, 2H), 3.06 (d, J=7.2 Hz, 2H), 3.32(td, J=2.0, 12.0 Hz, 2H), 3.50 (s, 3H), 3.74 (s, 6H), 3.90-3.98 (m, 2H),4.54 (s, 2H), 6.59 (dd, J=1.6, 7.2 Hz, 1H), 6.67 (s, 2H), 7.05 (dd,J=7.2, 8.8 Hz, 1H), 7.41 (dd, J=1.6, 8.8 Hz, 1H).

Similarly to Example 59, the compound of Example 60 was synthesized.

Example 60N-Cyclopropylmethyl-N-[7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethylamine

Yellow oil

¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 2H), 0.28-0.38 (m, 2H),0.80-0.90 (m, 1H), 1.58-1.68 (m, 1H), 1.88-1.96 (m, 1H), 2.20-2.30 (m,1H), 2.42 (s, 3H), 2.88-2.92 (m, 2H), 3.02-3.10 (m, 1H), 3.20-3.24 (m,1H), 3.47 (s, 3H), 3.58-3.82 (m, 4H), 3.71 (s, 6H), 4.52 (s, 2H), 6.57(dd, J=1.6, 7.2 Hz, 1H), 6.64 (s, 2H), 7.03 (dd, J=6.8, 8.8 Hz, 1H),7.38 (dd, J=1.6, 8.8 Hz, 1H).

Production Example 1X 2-Ethyl-3-iodopyrazolo[1,5-a]pyridine

N-Chlorosuccinimide (411 g, 3.08 mol) was gradually added to a mixtureof 2-ethylpyrazolo[1,5-a]pyridine (360 g, 2.46 mol), ethyl acetate (3600mL), water (1800 mL) and sodium iodide (480 g, 3.20 mol, 1.3equivalents) over a period of 30 minutes while cooling with ice, andthen the reaction mixture was stirred for 2 hours and 20 minutes at roomtemperature. After the reaction, water and ethyl acetate were added tothe reaction mixture and extraction was performed with ethyl acetate.The organic extract was washed twice with 10% aqueous sodiumthiosulfate, and then concentrated. Hexane was added to the residue, themixture was heated to dissolution and the resulting solution wasfiltered to remove insoluble residue. After then washing the hexanesolution with water, the hexane layer was concentrated, the residue wasdissolved in ethyl acetate and the solvent was evaporated to afford 663g of the title compound (98.9% yield).

¹H NMR (400 MHz, CDCl₃) δ 1.35 (t, J=7.7 Hz, 3H), 2.84 (q, J=7.7 Hz,2H), 6.72 (ddd, J=6.8, 6.8, 1.3 Hz, 1H), 7.15 (ddd, J=9.0, 6.8, 1.1 Hz,1H), 7.37 (ddd, J=9.0, 1.3 Hz, 1.3, 1H), 8.36 (ddd, J=6.8, 1.1, 1.1 Hz,1H).

Production Example 2X Tetrahydro-2H-4-pyrancarboxamide

Concentrated aqueous ammonia (50 mL) was added to methyltetrahydro-2H-pyran-4-carboxylate (50 g, 347 mmol) and the reactionmixture was stirred for 43.5 hours at room temperature. The reactionmixture was then cooled in an ice water bath, after which theprecipitate was filtered out and dried under reduced pressure at 40° C.to afford 33.4 g of the title compound (74.6% yield).

¹H NMR (400 MHz, DMSO-d₆) δ 1.45-1.62 (m, 4H), 2.28 (tt, J=11.1, 4.4 Hz,1H), 3.26 (ddd, J=11.4, 11.4, 2.7 Hz, 2H), 3.82 (br d, J=11.4 Hz, 2H),6.74 (br s, 1H), 7.21 (br s, 1H).

Production Example 3XN4-(2-Ethylpyrazolo[1,5-a]pyridin-3-yl)tetrahydro-2H-4-pyrancarboxamide

A mixture of 2-ethyl-3-iodopyrazolo[1,5-a]pyridine (350 g, 1.29 mol),tetrahydro-2H-4-pyrancarboxamide (249 g, 1.93 mol), copper iodide (49.0g, 258 mmol), tripotassium phosphate (hydrate) (546 g, 2.57 mol),1,2-cyclohexanediamine (mixture of cis and trans) (58.7 g, 514 mmol) andxylene (3500 mL) was stirred while heating at an external temperature of120° C. (oil bath). The reaction mixture was heated and stirred for 6hours, and then heating was terminated and upon reaching an internaltemperature of 61.5° C., hot water (58° C., 3500 mL) was added to thereaction mixture and stirring was continued overnight. After adding 28%aqueous ammonia (1050 mL) to the reaction mixture and stirring for 1hour, the precipitate was filtered out and washed with water (1750 mL)and ethyl acetate (1050 mL) and then dried under aeration at 60° C.overnight to afford 280 g of the title compound (major conformer:minorconformer=6:1) (79.6% yield).

Major Conformer

¹H NMR (400 MHz, CDCl₃) δ 1.33 (t, J=7.7 Hz, 3H), 1.88-2.05 (m, 4H),2.57-2.67 (m, 1H), 2.75 (q, J=7.7 Hz, 2H), 3.50 (ddd, J=11.4, 11.4, 2.9Hz, 2H), 4.09 (ddd, J=11.4, 4.0, 2.6 Hz, 2H), 6.68 (ddd, J=6.8, 6.8, 1.3Hz, 1H), 6.82 (br s, 1H), 7.07 (ddd, J=9.0, 6.8, 1.3 Hz, 1H), 7.29 (brd, J=9.0 Hz, 1H), 8.30 (d, J=6.8 Hz, 1H).

Minor Conformer

¹H NMR (400 MHz, CDCl₃) δ 1.34 (t, J=7.7 Hz, 3H), 1.40-1.50 (m, 2H),1.88-2.05 (m, 2H), 2.37-2.48 (m, 1H), 2.78 (q, J=7.7 Hz, 2H), 3.14 (ddd,J=11.9, 11.9, 1.8 Hz, 2H), 3.84-3.92 (m, 2H), 6.56 (br s, 1H), 6.80(ddd, J=6.8, 6.8, 1.3 Hz, 1H), 7.20 (br dd, J=9.0, 6.8 Hz, 1H), 7.34 (brd, J=9.0 Hz, 1H), 8.39 (d, J=6.8 Hz, 1H).

Production Example 4XN4-Cyclopropylmethyl-N4-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)tetrahydro-2H-4-pyrancarboxamide

A mixture ofN4-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)tetrahydro-2H-4-pyrancarboxamide(272 g, 915 mmol), potassium tert-butoxide (144 g, 1.28 mol) and1,2-dimethoxyethane (1750 mL) was heated and stirred at an externaltemperature of 40° C. (Bromomethyl)cyclopropane (161 g, 1.19 mol) wasthen added dropwise to the reaction mixture keeping the internaltemperature below 50° C. After heating and stirring for 4 hours, water(1250 mL) and toluene (3750 mL) were added to the reaction mixture. Theaqueous layer was removed, and then the organic extract was washed with10% brine (1250 mL) and water (1250 mL×2 times) in that order, andconcentrated under reduced pressure to afford 277 g of the titlecompound as a brown oil (92.6% yield).

¹H NMR (400 MHz, CDCl₃) δ 0.03-0.11 (m, 1H), 0.14-0.22 (m, 1H),0.32-0.46 (m, 2H), 0.85-0.98 (m, 1H), 1.36 (t, J=7.6 Hz, 3H), 1.29-1.40(m, 1H), 1.40-1.50 (m, 1H), 1.85 (ddd, J=16.3, 11.9, 4.4 Hz, 1H), 1.97(ddd, J=16.5, 11.9, 4.6 Hz, 1H), 2.41 (tt, J=11.5, 3.8 Hz, 1H),2.66-2.84 (m, 2H), 3.03 (ddd, J=11.9, 11.9, 2.2 Hz, 1H), 3.15 (ddd,J=11.9, 11.9, 2.2 Hz, 1H), 3.31 (dd, J=13.7, 7.3 Hz, 1H), 3.79 (dd,J=13.7, 7.3 Hz, 1H), 3.76-3.86 (m, 1H), 3.91 (ddd, J=11.9, 4.4, 2.0 Hz,1H), 6.79 (ddd, J=6.8, 6.8, 1.4 Hz, 1H), 7.17 (br dd, J=8.8, 6.8 Hz,1H), 7.33 (br d, J=8.8 Hz, 1H), 8.40 (d, J=6.8 Hz, 1H).

Production Example 5XN-Cyclopropylmethyl-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-tetrahydro-2H-4-pyranylmethylamine

A solution ofN4-cyclopropylmethyl-N4-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)tetrahydro-2H-4-pyrancarboxamide(220 g, 672 mmol) in tetrahydrofuran (1100 mL) was stirred at anexternal temperature of 55° C. (hot water bath). Aborane-tetrahydrofuran complex (1M solution, 1748 mL) was added dropwiseto the reaction mixture, and after heating and stirring for 2 hours, thereaction mixture was cooled in an ice bath and 2N hydrochloric acid (437mL) was added. The reaction mixture was then stirred for 1 hour at anexternal temperature of 50° C. (hot water bath). After the reactionterminated, a 5N aqueous sodium hydroxide solution (299 mL) was addeddropwise to the reaction mixture to adjust it to pH 8, and the aqueouslayer was removed. Toluene (2200 mL) was then added to the organicextract, and after washing the organic extract twice with water, it wasconcentrated under reduced pressure to afford 209 g of the titlecompound (99.2% yield).

¹H NMR (400 MHz, CDCl₃) δ −0.04-0.06 (m, 2H), 0.30-0.40 (m, 2H),0.73-0.86 (m, 1H), 1.18-1.36 (m, 2H), 1.33 (t, J=7.6 Hz, 3H), 1.46-1.60(m, 1H), 1.72 (br d, J=12.8 Hz, 2H), 2.82 (q, J=7.6 Hz, 2H), 2.84 (d,J=7.2 Hz, 2H), 3.01 (d, J=7.2 Hz, 2H), 3.28 (ddd, J=12.0, 12.0, 2.0 Hz,2H), 3.92 (br dd, J=12.0, 4.4 Hz, 2H), 6.59 (ddd, J=6.8, 6.8, 1.2 Hz,1H), 6.95 (ddd, J=8.8, 6.8, 1.2 Hz, 1H), 7.44 (ddd, J=8.8, 1.2, 1.2 Hz,1H), 8.29 (ddd, J=6.8, 1.2, 1.2 Hz, 1H).

Production Example 6XN-Cyclopropylmethyl-N-(2-ethyl-7-iodopyrazolo[1,5-a]pyridin-3-yl)-N-tetrahydro-2H-4-pyranylmethylamine

A solution ofN-cyclopropylmethyl-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-tetrahydro-2H-4-pyranylmethylamine(180 g, 574 mmol) in tetrahydrofuran (1620 mL) was cooled with dryice-ethanol bath. A 1.6M n-butyllithium-hexane solution (538 mL, 854mmol) was added dropwise to the solution at an internal temperature offrom −73° C. to −64.5° C. After stirring the reaction mixture for 1 hourat the same temperature, pentafluoroiodobenzene (115 mL, 861 mmol) wasadded dropwise. The reaction mixture was additionally stirred for 1 hourand 20 minutes, and then water/THF (1/1, v/v, 360 mL) was added thereto.Cooling was terminated, and then water (3600 mL) and heptane (3600 mL)were added to the reaction mixture, the aqueous layer was removed andthe organic extract was washed with water (3600 mL). A 5N aqueoushydrochloric acid solution (1800 mL) was then added to the organic layerand the aqueous layer was separated off. After cooling the aqueous layerin an ice bath and adding a 5N aqueous sodium hydroxide solution (1620mL), toluene (3600 mL) was further added to the reaction mixture and theorganic layer was separated off. The aqueous layer was extracted withtoluene (3600 mL), and both organic extracts were combined andconcentrated to afford 220 g of the title compound as a dark green oil(87.3% yield).

¹H NMR (400 MHz, CDCl₃) δ −0.02-0.05 (m, 2H), 0.33-0.40 (m, 2H),0.74-0.86 (m, 1H), 1.19-1.32 (m, 2H), 1.36 (t, J=7.6 Hz, 3H), 1.46-1.60(m, 1H), 1.71 (br d, J=13.2 Hz, 2H), 2.86 (d, J=6.8 Hz, 2H), 2.88 (q,J=7.6 Hz, 2H), 3.02 (d, J=6.8 Hz, 2H), 3.28 (ddd, J=11.6, 11.62.0 Hz,2H), 3.92 (br dd, J=11.6, 2.6 Hz, 2H), 6.71 (dd, J=8.8, 6.8 Hz, 1H),7.20 (dd, J=6.8, 1.2 Hz, 1H), 7.47 (dd, J=8.8, 1.2 Hz, 1H).

Production Example 7XN-Cyclopropylmethyl-N-(2-ethyl-7-iodopyrazolo[1,5-a]pyridin-3-yl)-N-tetrahydro-2H-4-pyranylmethylaminehydrochloride

A solution of concentrated hydrochloric acid (48.5 mL, 575 mmol) inisopropanol (270 mL) was added dropwise to a solution ofN-cyclopropylmethyl-N-(2-ethyl-7-iodopyrazolo[1,5-a]pyridin-3-yl)-N-tetrahydro-2H-4-pyranylmethylamine(220 g, 501 mmol) in dimethyl carbonate (3600 mL) over a period of 20minutes at room temperature, and the reaction mixture was stirred for 15hours at room temperature. The reaction mixture was then cooled in anice water bath, and dimethyl carbonate (900 mL) was added thereto. Afterstirring the reaction mixture for about 5 hours, the precipitated solidwas collected by filtration and washed with dimethyl carbonate (900 mL).It was then dried under reduced pressure at 50° C. to afford 250 g ofthe title compound (93.7% yield) as a solvate with dimethyl carbonateand isopropanol.

¹H NMR (400 MHz, CD₃OD) δ 0.08-0.40 (m, 2H), 0.42-0.56 (m, 2H),0.81-0.94 (m, 1H), 1.30-1.60 (m, 4H), 1.50 (t, J=7.5 Hz, 3H), 1.67-1.81(m, 1H), 3.06 (q, J=7.5 Hz, 2H), 3.24 (ddd, J=11.7, 11.72.4 Hz, 2H),3.56-3.76 (m, 4H), 3.82-3.90 (m, 2H), 7.20 (dd, J=8.8, 7.1 Hz, 1H), 7.66(d, J=7.1 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H).

Production Example 8X 2-Bromo-1,3-dimethoxy-5-(methoxymethyl)benzene

Mesyl chloride (34.5 mL, 446 mmol) was added to a solution of(4-bromo-3,5-dimethoxyphenyl)methanol (100 g, 405 mmol) andtriethylamine (67.5 mL, 484 mmol) in 1,2-dimethoxyethane (1000 mL) whilecooling with ice, and the reaction mixture was stirred for 30 minutes.After adding a 28% sodium methoxide in methanol (350 mL, 1.72 mol) tothe reaction mixture, it was further stirred for 3 hours at roomtemperature. Upon completion of the reaction, toluene (1000 mL) andwater (1000 mL) were added to the reaction mixture, the aqueous layerwas removed, and the organic extract was washed with water (1000 mL), 1Nhydrochloric acid (500 mL) and water (500 mL) in that order andconcentrated under reduced pressure to afford 105 g of the titlecompound as a colorless oil (99.5% yield).

Production Example 9X 2,6-Dimethoxy-4-(methoxymethyl)phenylboric acid

To a solution of 2-bromo-1,3-dimethoxy-5-(methoxymethyl)benzene (20.0 g,76.6 mmol) in tetrahydrofuran (200 mL) which had been cooled in a dryice-acetone bath was added 1.58M n-butyllithium in hexane (50.9 mL, 80.4mmol) under a nitrogen stream, and the reaction mixture was stirred for30 minutes. A solution of trimethoxyborane (8.75 g, 84.2 mmol) intetrahydrofuran (20 mL) was then added to the reaction mixture, and thereaction temperature was increased to 0° C. while stirring. After adding1N hydrochloric acid (200 mL) to the reaction mixture, it was stirredfor 30 minutes at room temperature. After the reaction terminated,toluene (200 mL) was added to the reaction mixture and the organic layerwas separated off, after which the aqueous layer was extracted withtoluene (100 mL). The combined organic extracts were washed with water(100 mL) and then concentrated under reduced pressure. The residue wasdissolved in tert-butyl methyl ether (75 mL) and the reaction mixturewas stirred for 30 minutes, after which heptane (223 mL) was addedthereto and the reaction mixture was further stirred for 2 hours. Theprecipitate was filtered out and washed with a mixed solution oftert-butyl methyl ether and heptane (1:3, 3.75 mL), and then dried at40° C. for 24 hours to afford 12.4 g of the title compound (71.8%yield).

Production Example 10X Methyl 4-bromo-3,5-dimethoxybenzoate

Potassium carbonate (359 g) was added to a solution of4-bromo-3,5-dihydroxybenzoic acid (127.5 g) in N,N-dimethylformamide(1020 mL) while cooling with ice bath, and then iodomethane (143 mL) wasfurther added. After removing the ice bath and stirring at roomtemperature for 17 hours, the reaction mixture was poured into icewater. The precipitated solid was collected by filtration and washedwith water, and then the residue was dissolved in ethyl acetate anddried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure to afford the title compound (133.2 g) as a whitesolid.

Production Example 11X (4-Bromo-3,5-dimethoxyphenyl)methanol

Lithium borohydride (20.8 g) was slowly added to a solution of methyl4-bromo-3,5-dimethoxybenzoate (133.2 g) in tetrahydrofuran (500 mL) atroom temperature, and the mixture was stirred for 3 hours while heatingto reflux. The reaction mixture was cooled to room temperature, icewater (1.5 L) was added, and then ethyl acetate (1.2 L) was furtheradded for extraction. The obtained organic extract was washed with brineand dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure to afford the title compound (118.8 g)as a white solid.

Production Example 12X 2-Bromo-1,3-dimethoxy-5-(methoxymethyl)benzene

Sodium hydride (60% in oil; 24.7 g) was added to a solution of(4-bromo-3,5-dimethoxyphenyl)methanol (118.8 g) in N,N-dimethylformamide(960 mL) while cooling with ice, and after stirring for 10 minutes,iodomethane (41.7 mL) was added dropwise, the temperature was increasedto room temperature and stirring was continued for 1 hour. The obtainedreaction mixture was poured into ice water (2.5 L), extraction wasperformed with ethyl acetate, the extract was washed with brine anddried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography and the title compound (121.3 g) was obtained as acolorless oil from the n-hexane:ethyl acetate (4:1) fraction.

Production Example 13X 2,6-Dimethoxy-4-(methoxymethyl)phenylboric acid

n-Butyllithium (2.64M hexane solution; 182 mL) was added dropwise to asolution of 2-bromo-1,3-dimethoxy-5-(methoxymethyl)benzene (121.3 g) intetrahydrofuran (730 mL) at −78° C., and the mixture was stirred for 20minutes. A solution of trimethoxyborane (61.7 mL) in tetrahydrofuran (20mL) was then added to the reaction mixture at −78° C. When internaltemperature was raised to −10° C., to the reaction mixture was addedsaturated aqueous ammonium chloride (730 mL), and stirring was continuedfor 15 minutes. The obtained reaction mixture was extracted with ethylacetate, the extract was washed with brine and dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatographyand the title compound (90.4 g) was obtained as a white solid from then-hexane:ethyl acetate (2:3) fraction.

¹H NMR (400 MHz, CDCl₃) δ 3.44 (s, 3H), 3.93 (s, 6H), 4.47 (s, 2H), 6.62(s, 2H), 7.19 (s, 2H).

Production Example 14X 2,6-Dimethoxy-4-(methoxymethyl)phenylboric acid

To a suspension of magnesium turnings (97.5 mg, 4.01 mmol) intetrahydrofuran (0.5 mL) containing a small amount of added iodine, wasadded approximately a tenth part of a solution of2-bromo-1,3-dimethoxy-5-(methoxymethyl)benzene (1.0 g, 3.82 mmol) intetrahydrofuran (1 mL) under a nitrogen atmosphere, and the mixture washeated in an oil bath at 70° C. The heating was terminated upon gentlereflux of the reaction mixture and fading of the iodine color. Tocontinue the reflux, the remaining solution of2-bromo-1,3-dimethoxy-5-(methoxymethyl)benzene in tetrahydrofuran wasadded dropwise to the reaction mixture. Upon completion of the dropwiseaddition, the reaction mixture was further heated to reflux for 1 hourand then cooled to room temperature. The reaction mixture was then addeddropwise to an ice-cooled solution of trimethyl borate (0.57 mL, 4.97mmol) in tetrahydrofuran (0.5 mL). Upon completion of the dropwiseaddition and stirring for 40 minutes while cooling with ice, the mixturewas stirred overnight at room temperature. An aqueous ammonium chloridesolution and methanol were then added to the reaction mixture.Quantitation by liquid chromatography confirmed that the title compoundhad been obtained at an 89% yield.

Production Example 1Y tert-ButylN-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)carbamate

To a solution of 2-ethyl-3-nitropyrazolo[1,5-a]pyridine (7.65 g, 40mmol) dissolved in a mixture of isopropyl alcohol (153 mL) and aceticacid (11.5 mL) was added di-tert-butyl dicarbonate (14 g, 64 mmol) and5% palladium-carbon (1.53 g, 50% wet), and reaction was conducted for 3hours at room temperature under a hydrogen atmosphere (0.3 MPa). Afterthe reaction, the reaction mixture was filtered and the obtainedfiltrate was evaporated. The residue was dissolved in ethyl acetate, andthe ethyl acetate solution was washed with aqueous sodium bicarbonateand brine. The organic extract was dried over magnesium sulfate andevaporated to dryness. Isopropyl alcohol (7.7 mL) and heptane (38.3 mL)were added thereto and the mixture was heated to 60° C. for dissolution.Slow cooling produced a precipitate, and then heptane (15.3 mL) wasadded thereto. After allowing the mixture to stand overnight and thenstirring for 30 minutes with ice bath, the precipitate was collected byfiltration and washed with heptane. The precipitate was dried underreduced pressure to afford 7.58 g of the title compound (71% yield).

Production Example 2Y tert-ButylN-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-tetrahydro-2H-4-pyranylmethylcarbamate

To a solution of tert-butylN-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)carbamate (12 g, 46 mmol) andpotassium tert-butoxide (6.2 g, 55 mmol) dissolved inN,N-dimethylformamide (120 mL) was added tetrahydropyran-4-ylmethylmethanesulfonate (10.7 g, 55 mmol) while cooling with ice, the reactionmixture was stirred for 1 hour, and then tetrahydrofuran (200 mL) wasfurther added and the reaction mixture was additionally stirred for 18hours. Water (200 mL) and ethyl acetate (500 mL) were then added to thereaction mixture, and the aqueous layer was separated and extracted withethyl acetate (300 mL). The combined organic extracts were washed withwater (300 mL, 3 times) and brine, dried over magnesium sulfate andevaporated under reduced pressure to afford 18 g of the title compoundas a yellow oil (>99% yield).

¹H NMR (CDCl₃) δ 1.33 (s, 9H), 1.37 (d, J=7.6 Hz, 3H), 1.10-1.80 (m,5H), 2.73 (q, J=7.6 Hz, 2H), 3.30-3.42 (m, 3H), 3.57-3.84 (m, 1H),3.90-4.02 (m, 2H), 6.70 (dd, J=6.8, 6.8 Hz, 1H), 7.10 (dd, J=7.1, 6.8Hz, 1H), 7.23 (d, J=7.1 Hz, 1H), 8.33 (d, J=6.8 Hz, 1H).

Production Example 3YN-(2-Ethylpyrazolo[1,5-a]pyridin-3-yl)-N-tetrahydro-2H-4-pyranylmethylaminehydrochloride

To a solution of tert-butylN-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-tetrahydro-2H-4-pyranylmethylcarbamate(17.5 g, 50 mmol) dissolved in 1,2-dimethoxyethane (175 mL) was added a4N hydrochloric acid-ethyl acetate solution (175 mL), and the reactionmixture was stirred for 3 hours at 45° C. The solvent was thenevaporated under reduced pressure, 1,2-dimethoxyethane (175 mL) andhexane (175 mL) were added to the residue, the mixture was cooled on iceand the precipitate was collected by filtration to afford 11.8 g of thetitle compound (87% yield).

¹H NMR (CDCl₃) δ 1.26-1.35 (m, 2H), 1.40 (t, J=8.0 Hz, 3H), 1.88 (d,J=12.7 Hz, 2H), 2.12-2.20 (m, 1H), 3.03 (q, J=8.0 Hz, 2H), 3.10-3.20 (m,4H), 3.81 (dd, J=11.5, 2.4 Hz, 2H), 6.80 (dd, J=6.8, 6.8 Hz, 1H), 7.18(dd, J=9.0, 6.8 Hz, 1H), 8.09 (d, J=9.0 Hz, 1H), 8.32 (d, J=6.8 Hz, 1H),11.70 (br s, 1H).

Production Example 4YN-Cyclopropylmethyl-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-tetrahydro-2H-4-pyranylmethylamine

A mixture ofN-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-tetrahydro-2H-4-pyranylmethylaminehydrochloride (10.3 g, 35 mmol) and potassium carbonate (5.8 g) in ethylacetate (150 mL) and water (30 mL) was stirred for 8 minutes at roomtemperature. The organic extract was separated and then washed withbrine, dried over magnesium sulfate and evaporated under reducedpressure to affordN-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-tetrahydro-2H-4-pyranylmethylamine(9.1 g). This compound was dissolved in tetrahydrofuran (180 mL), andthen cyclopropanecarbaldehyde (7.4 g, 106 mmol) and sodiumtriacetoxyborohydride (10.5 g, 49.7 mmol) were added and the reactionmixture was stirred for 10 minutes. After completion of the reaction,ethyl acetate (400 mL) and water (200 mL) were added to the reactionmixture and the organic extract was separated. After extracting theaqueous layer again with ethyl acetate (200 mL), the organic extractswere combined and washed with water (100 mL) and brine (100 mL). Theorganic extract was dried over magnesium sulfate and evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=6:1) to afford 11.9 g of the titlecompound as a yellow oil (>99% yield).

Production Example 5Y tert-ButylN-cyclopropylmethyl-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)carbamate

To a solution of tert-butyl N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)carbamate (4.93 g, 18.0 mmol) and potassium tert-butoxide (2.54 g, 22.6mmol) dissolved in N,N-dimethylformamide (49 mL) was added(bromomethyl)cyclopropane (2.02 mL, 20.8 mmol) dropwise. The reactionmixture was stirred at room temperature for 15 minutes, and then ethylacetate (50 mL), heptane (50 mL) and water (50 mL) were added and theorganic layer was separated off. The aqueous layer was then againextracted with heptane (30 mL). The combined organic extracts werewashed with water (25 mL×2 times) and 10% brine (10 mL). The organicextract was dried over magnesium sulfate and evaporated under reducedpressure to afford 6.5 g of the title compound (>99% yield).

¹H NMR (400 MHz, CDCl₃) δ 0.00-0.19 (m, 2H), 0.30-0.50 (m, 2H), 0.95 (brs, 1H), 1.20-1.60 (m, 9H), 1.34 (t, J=7.6 Hz, 3H), 2.75 (q, J=7.6 Hz,2H), 3.25-3.40 (m, 1H), 3.44-3.62 (m, 1H), 6.67 (t, J=6.8 Hz, 1H), 7.07(t, J=7.2 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 8.31 (d, J=7.2 Hz, 1H)

Production Example 6Y tert-ButylN-(7-bromo-2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-cyclopropylmethylcarbamate

A solution of n-butyllithium in hexane (1.6M, 3.88 mL, 6.18 mmol) wasadded dropwise to a solution of tert-butylN-cyclopropylmethyl-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)carbamate (1.5g, 4.76 mmol) in tetrahydrofuran (15 mL) at −70° C. After stirring thereaction mixture for 50 minutes at the same temperature,1,2-dibromotetrafluoroethane (1.0 mL, 8.33 mmol) was added dropwise tothe reaction mixture. The temperature of the reaction mixture was slowlyincreased and aqueous sodium bicarbonate was added at 0° C. The reactionmixture was extracted with ethyl acetate, and the organic extract waswashed with brine, dried over magnesium sulfate and evaporated. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=8:1) to afford 1.65 g of the title compound as a yellow oil(87.8% yield).

¹H NMR (400 MHz, CDCl₃) δ 0.00-0.20 (m, 2H), 0.39 (m, 2H), 0.95 (m, 1H),1.25-1.60 (m, 9H), 1.35 (t, J=8.0 Hz, 3H), 2.56 (q, J=8.0 Hz, 2H),3.20-3.35 (m, 1H), 3.50-3.65 (m, 1H), 6.93-7.04 (m, 2H), 7.35 (dd,J=1.6, 8.4 Hz, 1H).

Production Example 7Y tert-ButylN-cyclopropylmethyl-N-7-(2,6-dimethoxy-4-(methoxymethyl)phenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-ylcarbamate

After adding 1,2-dimethoxyethane (26.7 mL) and water (13.4 mL) to amixture of tert-butylN-(7-bromo-2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-cyclopropylmethylcarbamate(422 mg, 1.34 mmol), 2,6-dimethoxy-4-(methoxymethyl)phenylboric acid(399 mg, 1.74 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg,0.20 mmol) and barium hydroxide octahydrate (634 mg, 2.0 mmol), themixture was degassed under reduced pressure at 0° C. while stirring. Thereaction mixture was heated to 90° C. and then stirred for 90 minutes.After the reaction, water was added to the reaction mixture andextracted with ethyl acetate. The organic extract was washed with brine,dried over magnesium sulfate and evaporated. The residue was purified bysilica gel column chromatography (n-hexane:ethyl acetate=4:1-2:1) andthen suspended and purified with heptane to afford 487 mg of the titlecompound (73% yield).

¹H NMR (400 MHz, CDCl₃) δ 0.10-0.22 (m, 2H), 0.35-0.50 (m, 2H), 1.15 (m,1H), 1.24 (t, J=7.6 Hz, 3H), 1.20-1.68 (m, 9H), 1.62 (s, 2H), 2.70 (q,J=7.6 Hz, 2H), 3.49 (s, 3H), 3.68-3.78 (m, 6H), 4.53 (s, 2H), 6.64-6.73(m, 3H), 7.11 (t, J=8.0 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H).

Production Example 8YN-Cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-ylamine

A mixture of tert-butylN-cyclopropylmethyl-N-7-(2,6-dimethoxy-4-(methoxymethyl)phenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-ylcarbamate(20 mg, 0.04 mmol) in trifluoroacetic acid (1.0 mL) was stirred for 30minutes at room temperature. A 5N aqueous sodium hydroxide was added tothe reaction mixture for neutralization, and then extracted with ethylacetate. The organic extract was washed with aqueous sodium bicarbonateand brine in that order and dried over magnesium sulfate. This wasevaporated under reduced pressure to afford 13 mg of the title compound(81% yield).

¹H NMR (400 MHz, CDCl₃) δ 0.18 (q, J=4.4 Hz, 2H), 0.45-0.55 (m, 2H),1.10-1.30 (m, 1H), 1.23 (t, J=7.2 Hz, 3H), 2.10 (br s, 1H), 2.75 (q,J=7.2 Hz, 2H), 2.89 (d, J=6.8 Hz, 2H), 3.47 (s, 3H), 3.70 (s, 6H), 4.51(s, 2H), 6.54 (dd, J=0.8, 6.8 Hz, 1H), 6.66 (s, 2H), 7.00 (dd, J=6.8,9.2 Hz, 1H), 7.40 (dd, J=0.8, 8.4 Hz, 1H).

Production Example 9Y 7-Bromo-2-ethylpyrazolo[1,5-a]pyridine

A solution of 2-ethylpyrazolo[1,5-a]pyridine (5.0 g, 34.2 mmol) intetrahydrofuran (50 mL) was cooled to below −70° C. under a nitrogenstream, and then a solution of n-butyllithium in hexane (32.5 mL, 1.58Msolution, 51.4 mmol) was added dropwise at below −60° C. After stirringfor 1 hour, bromopentafluorobenzene (9.3 g, 37.7 mmol) was addeddropwise to the reaction mixture at below −60° C. The reaction mixturewas stirred for 2 hours at below −70° C., and then water (50 mL) wasadded to the reaction mixture and the temperature was raised to roomtemperature. Ethyl acetate (50 mL) and water (50 mL) were added thereto,and extraction was performed with ethyl acetate. The organic extract waswashed twice with 5% brine (50 mL) and dried over anhydrous magnesiumsulfate, and then the solvent was evaporated under reduced pressure toafford 6.9 g of the title compound.

Production Example 11Y 7-Bromo-2-ethyl-3-nitropyrazolo[1,5-a]pyridine

Fuming nitric acid (1.7 mL) was added dropwise to a solution of7-bromo-2-ethylpyrazolo[1,5-a]pyridine (6.9 g, 34.2 mmol) inconcentrated sulfuric acid (13.8 mL) at an internal temperature of below30° C. while cooling with ice. After stirring the reaction mixture for30 minutes, it was added to ice water (138 mL) and the precipitate wasfiltered out. The obtained precipitate was added ethyl acetate (226 mL)and methanol (38 mL), and the mixture was heated to 70° C., and then theprecipitate was collected by filtration while cooling with ice. Thesolvent of the obtained filtrate was evaporated under reduced pressure,and the concentrated residue was recrystallized from heptane-ethylacetate (1:1) to afford 2.4 g of the title compound as light browncrystals (31% yield).

Production Example 11Y7-[2,6-Dimethoxy-4-(methoxymethyl)phenyl]-2-ethyl-3-nitropyrazolo[1,5-a]pyridine

A mixture of 7-bromo-2-ethyl-3-nitropyrazolo[1,5-a]pyridine (3.0 g, 11.1mmol), 2,6-dimethoxy-4-(methoxymethyl)phenylboric acid (5.0 g, 22.2mmol), palladium acetate (125 mg, 0.55 mmol), triphenylphosphine (578mg, 2.22 mmol), tripotassium phosphate hydrate (5.3 g, 22.2 mmol) and1,2-dimethoxyethane (30 mL) was heated to reflux for 14 hours under anitrogen atmosphere. The reaction mixture was cooled to roomtemperature, ethyl acetate (100 mL) and water (50 mL) were added and theorganic layer was separated off. The organic extract was then washedwith 10% brine (50 mL), 1N hydrochloric acid (50 mL) and 10% aqueousammonia (50 mL) in that order. The organic extract was dried overanhydrous magnesium sulfate and the solvent was evaporated under reducedpressure. The obtained concentrated residue was purified by silica gelcolumn chromatography to afford 3.45 g of the title compound (84%yield).

¹H NMR (400 MHz, CDCl₃) δ 1.25 (t, J=7.4 Hz, 3H), 3.15 (q, J=7.4 Hz,2H), 3.50 (s, 3H), 3.78 (s, 6H), 4.57 (s, 2H), 6.65 (s, 2H), 7.05 (dd,J=7.0, 1.0 Hz, 1H), 7.66 (dd, J=9.0, 7.0 Hz, 1H), 8.36 (dd, J=9.0, 1.0Hz, 1H).

Production Example 12Y7-[2,6-Dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridine-3-amine

A mixture of7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethyl-3-nitropyrazolo[1,5-a]pyridine(850 mg, 2.3 mmol), 10% palladium-carbon (50% wet, 330 mg) and methanol(19 mL) was stirred for 13 hours at 50° C. under a hydrogen atmosphereat atmospheric pressure. After cooling the reaction mixture to roomtemperature, the reaction mixture was filtered through celite to removethe catalyst. The solvent of the obtained filtrate was evaporated underreduced pressure to afford 3.45 g of the title compound (84% yield).

¹H NMR (400 MHz, CDCl₃) δ 1.24 (t, J=7.4 Hz, 3H), 1.46-1.96 (br s, 2H),2.76 (q, J=7.4 Hz, 2H), 3.48 (s, 3H), 3.70 (s, 6H), 4.52 (s, 2H), 6.52(d, J=6.3 Hz, 1H), 6.66 (s, 2H), 6.99 (dd, J=8.6, 6.3 Hz, 1H), 7.32 (d,J=8.6 Hz, 1H).

Production Example 13YN-Cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-ylamine

A mixture of7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridine-3-amine(400 mg, 1.17 mmol), cyclopropanecarbaldehyde (0.122 mL, 1.64 mmol) andtetrahydrofuran (2 mL) was heated for 1 hour at 50° C. The reactionmixture was then added dropwise to ice-cooled diisobutylaluminum hydride(1M toluene solution, 3.51 mL, 3.51 mmol). The reaction mixture wasstirred for 20 minutes, and then 1N hydrochloric acid (2 mL) and ethylacetate (20 mL) were added to the reaction mixture and extraction wasperformed with ethyl acetate. The organic extract was washed twice withwater (10 mL) and dried over anhydrous magnesium sulfate, and then thesolvent was evaporated under reduced pressure. The obtained concentratedresidue was recrystallized from heptane:ethyl acetate (10:1) to afford290 mg of the title compound as white crystals (63% yield).

¹H NMR (400 MHz, CDCl₃) δ 0.18 (q, J=4.4 Hz, 2H), 0.45-0.55 (m, 2H),1.10-1.30 (m, 1H), 1.23 (t, J=7.2 Hz, 3H), 2.10 (br s, 1H), 2.75 (q,J=7.2 Hz, 2H), 2.89 (d, J=6.8 Hz, 2H), 3.47 (s, 3H), 3.70 (s, 6H), 4.51(s, 2H), 6.54 (dd, J=6.8, 0.8 Hz, 1H), 6.66 (s, 2H), 7.00 (dd, J=9.2,6.8 Hz, 1H), 7.40 (dd, J=8.4, 0.8 Hz, 1H).

Example 1XN-Cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylaminetosylate

A mixture ofN-cyclopropylmethyl-N-(2-ethyl-7-iodopyrazolo[1,5-a]pyridin-3-yl)-N-(tetrahydro-2H-4-pyranylmethyl)aminehydrochloride (193 g, 405 mmol),2,6-dimethoxy-4-(methoxymethyl)phenylboric acid (143 g, 105 mmol, 1.56equivalents), palladium acetate (4.7 g, 21 mmol, 5 mol %),triphenylphosphine (27.6 g, 105 mmol, 26 mol %), potassium carbonate(203 g, 1.47 mmol, 3.63 equivalents), 1,2-dimethoxyethane (6667 mL) andwater (3333 mL) in a flask was heated in a 100° C. oil bath, thereaction system was purged with nitrogen gas. After about 6 hours fromthe start of reflux, the reaction mixture was cooled to roomtemperature.

Next, toluene (2000 mL) was added to the reaction mixture and theseparated aqueous layer was removed. The toluene layer was extractedtwice with 5N hydrochloric acid (first time: 3000 mL, second time: 1000mL). Isopropyl acetate (2000 mL) was added to the aqueous layer, andwhile cooling in an ice water bath, a 5N aqueous sodium hydroxidesolution (4200 mL) was added for adjustment to pH 14, and the isopropylacetate layer was separated off. The isopropyl acetate layer was thenwashed with a 10% aqueous ethylenediamine solution (2000 mL, 3 times)and water (2000 mL, 2 times), and after concentration, ethanol (400 mL)was added for azeotropic distillation and the reaction mixture wasconcentrated to afford 207 g of a green solid.

The residue was dissolved in ethanol (1720 mL) while heating, and asolution of p-toluenesulfonic acid monohydrate (65.5 g, 344 mmol) inethanol (170 mL) was added dropwise over a period of 3 minutes at aninternal temperature of 60° C. After allowing the mixture to cool whilestirring, seed crystals (100 mg) were added when the internaltemperature reached 35° C. After 30 minutes, the mixture was cooled in athermostat bath at 7° C. and stirred for 15 hours and 45 minutes. Theprecipitated crystals were then filtered out and washed with isopropanol(400 mL). The crystals were dried under reduced pressure at 60° C. for3.5 hours to afford 214 g of the title compound as white crystals (79.5%yield).

Example 2XN-Cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine

A mixture ofN-cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-ylamine(20 mg, 0.05 mmol), sodium iodide (75 mg, 0.50 mmol),tetrahydro-2H-4-pyranylmethyl methanesulfonate (49 mg, 0.25 mmol) andsodium carbonate (10 mg) dissolved in dimethylformamide (0.5 mL) wasstirred for 90 minutes at room temperature. Water and ethyl acetate werethen added to the reaction mixture and extraction was performed withethyl acetate. The organic extract was dried over magnesium sulfate andthen evaporated. The residue was purified by silica gel columnchromatography to afford 21 mg of the title compound (84% yield).

Example 3XN-Cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylaminehydrochloride

To a solution ofN-cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine(2.2 g) dissolved in ethyl acetate (30 mL) was added 4N hydrochloricacid-ethyl acetate (1.17 mL) at room temperature, the reaction mixturewas stirred while cooling with ice, and the precipitate was collected byfiltration to afford a crude product of the title compound (2.2 g) as awhite powder.

The obtained crude product (2.2 g) was recrystallized from a mixedsolvent of t-butyl methyl ether (500 mL) and ethyl acetate (700 mL) toafford the title compound (1.5 g).

¹H NMR (400 MHz, DMSO-d₆, at 100° C.) δ −0.04-0.10 (m, 2H), 0.30-0.38(m, 2H), 0.77-0.87 (m, 1H), 1.14-1.25 (m, 5H), 1.55-1.70 (m, 3H), 2.73(q, J=8 Hz, 2H), 2.99 (br s, 2H), 3.14 (br s, 2H), 3.21 (br ddd, J=11,11, 1 Hz, 2H), 3.41 (s, 3H), 3.64 (s, 6H), 3.80 (ddd, J=11, 6, 4 Hz,2H), 4.50 (s, 2H), 6.59 (br d, J=7 Hz, 1H), 6.74 (s, 2H), 7.11 (br t,J=7 Hz, 1H), 7.59 (br s, 1H).

Example 4XN-Cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylaminesulfate

To a solution ofN-cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine(2.01 g) dissolved in 2-propanol (50 mL) was added 3M sulfuric acid(0.68 mL) while cooling with ice and the reaction mixture was stirred.The reaction mixture was then evaporated under reduced pressure toafford a crude product of the title compound.

The obtained crude product was recrystallized from a mixed solvent of2-propanol (40 mL) and ethanol (20 mL) to afford the title compound(1.04 g).

¹H NMR (400 MHz, DMSO-d₆, at 100° C.) δ −0.02-0.07 (m, 2H), 0.32-0.38(m, 2H), 0.75-0.87 (m, 1H), 1.14-1.25 (m, 5H), 1.55-1.70 (m, 3H), 2.70(q, J=8 Hz, 2H), 2.97 (br s, 2H), 3.12 (br s, 2H), 3.22 (br ddd, J=11,11, 2 Hz, 2H), 3.41 (s, 3H), 3.64 (s, 6H), 3.80 (br d, J=11 Hz, 2H),4.50 (s, 2H), 6.58 (br d, J=7 Hz, 1H), 6.74 (s, 2H), 7.10 (br dd, J=8, 7Hz, 1H), 7.54 (br d, J=8 Hz, 1H).

Example 5XN-Cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylaminemethanesulfonate

To a solution ofN-cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine(1.78 g) dissolved in ethyl acetate (40 mL) was added methanesulfonicacid (234 μL), and the reaction mixture was stirred at room temperatureand evaporated under reduced pressure. The obtained residue was washedwith a mixed solvent of n-hexane:ethyl acetate (10:1) to afford a crudeproduct of the title compound (2.1 g).

The obtained crude product (2.1 g) was recrystallized from a mixedsolvent of t-butyl methyl ether (400 mL) and ethyl acetate (150 mL) toafford the title compound (1.6 g).

¹H NMR (400 MHz, DMSO-d₆, at 100° C.) δ −0.03-0.07 (m, 2H), 0.32-0.40(m, 2H), 0.75-0.87 (m, 1H), 1.12-1.25 (m, 5H), 1.53-1.70 (m, 3H), 2.41(s, 3H), 2.70 (q, J=8 Hz, 2H), 2.97 (br s, 2H), 3.11 (br s, 2H), 3.22(br ddd, J=11, 11, 1 Hz, 2H), 3.41 (s, 3H), 3.64 (s, 6H), 3.80 (br d,J=11 Hz, 2H), 4.50 (s, 2H), 6.57 (br d, J=6 Hz, 1H), 6.74 (s, 2H), 7.09(br dd, J=7, 6 Hz, 1H), 7.53 (br d, J=7 Hz, 1H).

Example 6XN-Cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylaminetosylate

To a solution ofN-cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine(1.6 g) dissolved in ethyl acetate (25 mL) was added p-toluenesulfonicacid monohydrate (617 mg), and the reaction mixture was stirred at roomtemperature. The precipitate was filtered out to afford a crude productof the title compound (2.18 g).

The obtained crude product (2.18 g) was recrystallized from a mixedsolvent of t-butyl methyl ether (640 mL) and ethyl acetate (770 mL) toafford the title compound (1.9 g).

¹H NMR (400 MHz, DMSO-d₆, at 100° C.) δ −0.03-0.07 (m, 2H), 0.30-0.40(m, 2H), 0.75-0.87 (m, 1H), 1.14-1.25 (m, 5H), 1.53-1.70 (m, 3H), 2.29(s, 3H), 2.70 (q, J=8 Hz, 2H), 2.97 (br s, 2H), 3.11 (br s, 2H), 3.22(br dd, J=11, 11 Hz, 2H), 3.41 (s, 3H), 3.64 (s, 6H), 3.80 (br d, J=11Hz, 2H), 4.50 (s, 2H), 6.58 (br d, J=6 Hz, 1H), 6.74 (s, 2H), 7.06-7.14(m, 3H), 7.49-7.58 (m, 3H).

Example 7XN-Cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylaminetosylate

To a solution ofN-cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine(500 mg) dissolved in ethanol (5 mL) was added a solution ofp-toluenesulfonic acid monohydrate (172 mg) in ethanol (1 mL) whileheating to reflux, and the reaction mixture was stirred while allowingit to cool to room temperature. After further cooling the reactionmixture to an internal temperature of −20° C., the precipitated crystalswere filtered out to afford the title compound (629 mg).

Example 8XN-Cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylaminehydrobromide

After adding a 48% aqueous hydrobromic acid solution (0.69 mL) to asolution ofN-cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine(2.0 g) in ethyl acetate (20 mL), the reaction mixture was vigorouslystirred at room temperature. The obtained precipitate was filtered outto afford a crude product of the title compound (2.34 g).

The obtained crude product (2.34 g) was recrystallized from ethanol (60mL) to afford the title compound (2.14 g).

¹H NMR (400 MHz, DMSO-d₆, at 100° C.) δ −0.03-0.07 (m, 2H), 0.30-0.40(m, 2H), 0.75-0.87 (m, 1H), 1.14-1.24 (m, 5H), 1.55-1.70 (m, 3H), 2.71(q, J=8 Hz, 2H), 2.98 (br s, 2H), 3.13 (br s, 2H), 3.21 (br ddd, J=11,11, 1 Hz, 2H), 3.41 (s, 3H), 3.64 (s, 6H), 3.80 (br d, J=11 Hz, 2H),4.50 (s, 2H), 6.59 (br d, J=6 Hz, 1H), 6.74 (s, 2H), 7.10 (br s, 1H),7.56 (br s, 1H).

Example 9XN-Cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylaminebenzenesulfonate

To a solution ofN-cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine(320 mg) dissolved in ethyl acetate (10 mL) was added benzenesulfonicacid monohydrate (108 mg), and the reaction mixture was stirred at roomtemperature. The obtained precipitate was filtered out to afford a crudeproduct of the title compound (330 mg).

The obtained crude product (330 mg) was recrystallized from a mixedsolvent of t-butyl methyl ether (70 mL) and ethyl acetate (80 mL) toafford the title compound (106 mg).

¹H NMR (400 MHz, DMSO-d₆, at 100° C.) δ −0.03-0.07 (m, 2H), 0.30-0.40(m, 2H), 0.75-0.87 (m, 1H), 1.14-1.25 (m, 5H), 1.55-1.70 (m, 3H), 2.70(q, J=8 Hz, 2H), 2.97 (br s, 2H), 3.12 (br s, 2H), 3.22 (br dd, J=11, 11Hz, 2H), 3.41 (s, 3H), 3.64 (s, 6H), 3.80 (br d, J=11 Hz, 2H), 4.50 (s,2H), 6.57 (br d, J=8 Hz, 1H), 6.74 (s, 2H), 7.10 (br dd, J=8, 8 Hz, 1H),7.23-7.32 (m, 3H), 7.54 (br d, J=8 Hz, 1H), 7.64 (dd, J=8, 2 Hz, 2H).

Example 10XN-Cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylamineethanesulfonate

To a solution ofN-cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine(350 mg) dissolved in a mixture of ethyl acetate (5 mL) and tert-butylmethyl ether (5 mL) was added ethanesulfonic acid (83 mg), and thereaction mixture was stirred at room temperature. The obtainedprecipitate was filtered out to afford a crude product of the titlecompound (355 mg).

The obtained crude product (355 mg) was recrystallized from a mixedsolvent of t-butyl methyl ether (40 mL) and ethyl acetate (40 mL) toafford the title compound (250 mg).

¹H NMR (400 MHz, DMSO-d₆, at 100° C.) δ −0.03-0.07 (m, 2H), 0.30-0.40(m, 2H), 0.75-0.87 (m, 1H), 1.10-1.25 (m, 8H), 1.55-1.70 (m, 3H), 2.52(q, J=7 Hz, 2H), 2.70 (q, J=8 Hz, 2H), 2.95 (br s, 2H), 3.11 (br s, 2H),3.22 (br dd, J 12, 12 Hz, 2H), 3.41 (s, 3H), 3.64 (s, 6H), 3.80 (br d,J=12 Hz, 2H), 4.50 (s, 2H), 6.57 (br d, J=7 Hz, 1H), 6.74 (s, 2H), 7.09(br dd, J=8, 7 Hz, 1H), 7.53 (br d, J=8 Hz, 1H).

Preparation Examples

The following are examples of formulating preparations of pharmaceuticalcompositions comprising compounds of the present invention.

Preparation Method

After mixing a compound of the invention(N-cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylaminetosylate), mannitol, crospovidone and hydroxypropylcellulose, anappropriate amount of purified water was used for wet granulation. Thegranulated product was dried and then size-controlled. Crospovidone andmagnesium stearate were placed with the granules prior to mixing andtableting. The obtained tablets were film coated with an aqueoussolution of a coating agent (a mixture of hydroxypropylmethylcellulose,talc, Macrogol 6000, titanium oxide and iron sesquioxide). The amountsof materials used per tablet are shown in Table 1. TABLE 1 PreparationExamples: Amounts of materials used per tablets (mg) 0.5 mg 5 mg 25 mgMaterial Purpose tablet tablet tablet The compound of major 0.675 6.7533.75 the present invention *1 ingredient Mannitol excipient 170.925164.85 137.85 Crospovidone disintegrator 10 10 10 Hydroxypropylcellulose binder 6 6 6 Purified water solvent q.s. q.s. q.s. Subtotal —187.6 187.6 187.6 Crospovidone disintegrator 10 10 10 Magnesium stearatelubricant 2.4 2.4 2.4 Subtotal — 200 200 200 Coating agent *2 coatingagent 8 8 8 Purified water solvent q.s. q.s. q.s. Total — 208 208 208*1N-cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylaminetosylate*2 Mixture of hydroxypropylmethylcellulose, talc, Macrogol 6000,titanium oxide and iron sesquioxide

Test Examples

The corticotropin releasing hormone receptor (CRFR) binding affinities,cAMP production inhibitions, antianxiety effects and drug metabolizingenzyme inducibilities of the compounds of the invention were evaluated.The test methods and results were as follows.

Test Example 1 CRFR Binding Experiment

(1) Preparation of CRFR1-Expressing Cells:

The membrane fraction of human CRFR1 high-expressing cells was used asthe material for a CRFR binding experiment. The CRFR-expressing cellswere prepared in the following manner. The full-length CRFR1 gene wasobtained by PCR using human brain cDNA library (QuickClone™ Clontech).The obtained DNA fragment was inserted into a cloning vector and thenucleotide sequence was ligated. cDNA having the proper nucleotidesequence was relinked to an expression vector (pcDNA3.1™, Invitrogen).The CRFR1 expression vector was introduced into HEK293 cell, and theresistant cells which proliferated in culture medium containing G418 (1mg/ml) were cloned by the limiting dilution method. Out of the clonedcells, cells having high binding affinity between the membrane fractionper unit of protein and sauvagine was selected according to thefollowing binding experiment. And the selected cells were used for theexperiments.

(2) Preparation of Membrane Fraction:

The cloned cells obtained in (1) were collected and suspended in chilledmembrane buffer (50 mM Tris-HCl, 5 mM MgCl₂, 2 mM EGTA, 1 mM DTT,protease inhibitor cocktail (COMPLETE™, Roche Diagnostics), pH 7.4), andafter disrupting the cells with a Polytron (KINEMATICA) (level 5,seconds, 4 times, ice cooling), they were centrifuged (13,000 rpm(18,000×g), 30 minutes, 4° C.) to precipitate the cell membranes. Theprecipitated cell membranes were suspended in membrane buffer, and weredisrupted with the Polytron (level 4, 20-30 seconds, ice cooling) toprepare a dispersed suspension. The protein contents of the dispersedsuspension were quantitated and this was diluted with membrane buffercontaining 0.1% BSA to a protein concentration of 200 μg/ml, for use asthe cell membrane fraction.

(3) Binding Experiment:

A CRF binding experiment was conducted by SPA™ (Amersham Pharmacia)method using a 96-well plate. The experiment was conducted according tothe instructions for SPA beads. After allowing 5 μg of the cell membranefraction protein, 1 mg of SPA beads and 100 pM of ¹²⁵I-CRF (PerkinElmer) to stand at room temperature for 2 hours or longer in thepresence of a test compound and then centrifuging (1,200 rpm (260×g), 5minutes, room temperature), the radioactivity of each well was measuredwith TopCount™ (Packard).

(4) Calculation of Binding Affinity:

The radioactivity with addition of 2.000-fold excess of nonradioactivesauvagine as non-specific binding was subtracted from each value, andeach value was represented as a percentage (% of control), where 100%was defined as the radioactivity with no addition of test compounds(control). The concentration exhibiting 50% (% of control) wasdetermined from a graph plotted with the test compound concentration onthe horizontal axis and the percentage (% of control) on the verticalaxis, as the IC₅₀ value.

Test Example 2 Camp Production Inhibition Experiment Using AtT-20 Cells

(1) Test Procedure:

AtT-20 cell is a cell-line derived from mouse pituitary gland tumor,which is known to respond to corticotropin releasing hormone (CRF), toproduce cAMP by activation of the intracellular adenylate cyclasesystem, and to release adrenocorticotropic hormone (ACTH) (Biochem.Biophys. Res. Com., 106, 1364-1371, 1982). In this experiment, AtT-20cells (1×10⁵) were suspended in D-MEM (0.1% FBS) and seeded in a 96-wellplate, and then 1 mM (final concentration) phosphodiesterase inhibitor(IBMX, Calbiochem) was added prior to incubation for 30 minutes at 37°C. The diluted test compound solution was then added prior to incubationfor 30 minutes at 37° C., and CRF (final concentration: 30 nM) was addedprior to further incubation for 30 minutes at 37° C. The cells werecollected by centrifugation (1,800 rpm (630×g), 5 minutes), and thenlysed with lysis buffer (0.2% dodecyltrimethylammonium bromide), and theintracellular cAMP production was assayed by HTRF method. cAMP kit HTRF(Nihon Schering) was used for the cAMP assay.

(2) Calculation of cAMP Production Inhibitory Activity:

The obtained data were processed in the following manner. The cAMPproduction of each sample was represented as a percentage (% ofcontrol), with the CRF (final concentration: 30 nM)-added cells definedas 100% (control). The concentration exhibiting 50% (% of control) wasdetermined from a graph plotted with the test compound concentration onthe horizontal axis and the percentage (% of control) on the verticalaxis, as the IC₅₀ value.

<Test Results>

In Test Example 1, all of the compounds of the present invention(Examples 1-9, 11-14, 18, 20-27, 29, 31-34, 37, 38, 40, 43, 44, 46-51,53-60) exhibited excellent binding affinity for CRFR1. In Test Example2, all of the compounds of the present invention (Examples 1-9, 11-14,18, 20-24, 26, 27, 29, 32-34, 37, 38, 40, 43, 44, 46-51, 53-60)exhibited excellent inhibitory effects on CRF-induced cAMP production.Some of the results are shown in Table 2. TABLE 2 CRF1 receptor cAMPproduction Compound No. binding affinity activity (Example No.) IC₅₀(nM) IC₅₀ (nM) Example 1 71 4 Example 3 49 5.1 Example 13 90 11 Example23 50 6 Example 47 50 50 Example 59 52 3.5 Example 60 30 3.5

Test Example 3 Evaluation of Antianxiety Effect by Mice in Light/DarkChamber

(1) Test procedure:

The test of mice in light-dark chamber was carried out according to amodified method of Belzung C., Misslin R., Vogel E. et al. (Reference;Behavioural effects of the benzodiazepine receptor partial agonistRO16-6028 in mice, Psychopharmacology, 97, 388-391, 1989). The testapparatus used was a light/dark chamber comprising a covered blackacrylic chamber (dark chamber; 15×10×20 cm), an uncovered white acrylicchamber (light chamber; 15×20×20 cm) and a black acrylic tunnel(10×7×4.5 cm) which connects dark chamber and light chamber and enablesa mouse to freely move back and forth between the dark chamber and lightchamber. In this test apparatus, however, a transparent acrylic polymerwas used for the front side (20×20 cm) and back side (20×20 cm) of thelight box to allow observation of the behavior. After settingillumination on the floor of the light box to an illuminance of 150 Lux,5-week-old male Balb/c mice (purchased from Nihon Charles River) wereintroduced into the dark box at the beginning of the test. For the test,the tested compound was suspended in a 0.5% aqueous methylcellulosesolution and orally administered to the test animals one hour prior tothe start of the test.

(2) Calculation of Antianxiety Effect:

The behavior of the mice was observed for 5 minutes after the start ofthe test. The light residence time was measured as an indicator of theantianxiety effect, with “light residence” defined as the state in whichthe limbs of the mice were on the floor of the light box. The minimumdose which significantly lengthened the light residence time withrespect to the vehicle-administered group was determined as the minimumeffective dose (MED). The statistical significance between thevehicle-administered group and the test compound-administered groups wasanalyzed by a Dunnett-type multiple comparison after one-way analysis ofvariance when multiple doses were set for the same test, and by theMann-Whitney U test when only one dose was set.

<Test Results>

N-Cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-2H-4-pyranylmethylamineexhibited an excellent effect based on evaluation of the antianxietyeffect in the test of mice in light/dark chamber, with an MED value of10 mg/kg.

Test Example 4 Evaluation of Drug Metabolizing Enzyme (CYP3A4)Inducibility Using Cryopreserved Human Hepatocyte

(1) Test Procedure:

Cryopreserved hepatocytes (In Vitro Technology) were rapidly thawedwhile stirring at 37° C., and then ice-cooled William's Medium E (10%FBS, +PSG) was slowly added to the cells prior to centrifugation at 500rpm for 5 minutes. After removing the supernatant, the obtainedhepatocytes were diluted with ice-cooled William's Medium E to aconcentration of 5×10⁵ cells/mL, seeded on a 48-well collagen coatedplate (BD Biosciences) at 1×10⁵ cells/cm² and incubated for about 24hours at 37° C., 5% CO₂, after which the medium was changed withHepato-STIM™ (BD Biosciences) (+EGF, PSG, −FBS) and culture wasmaintained for another 24 hours under conditions of 37° C., 5% CO₂. Atapproximately 48 hours after the cell seeding, the test compound orrifampicin (SIGMA, positive control) in the form of a diluted solution(using Hepato-STIM™ (+EGF, PSG, −FBS)) was added, hepatocyte wereincubated for about 24 hours under conditions of 37° C., 5% CO₂, and theculture medium was changed with medium containing a freshly prepareddilution of the test compound or rifampicin prior to further incubationfor 24 hours under the same conditions. After incubation, the cells werewashed once with PBS, and the total RNA was extracted using a QiagenRNeasy Mini kit (Qiagen). The cDNA was synthesized byreverse-transcription of extracted using TaqMan Reverse TranscriptionReagents (Applied Biosystems). The reverse transcription reaction wascarried out using oligo dT as primer, with treatment at 25° C. for 10minutes followed by treatment at 48° C. for 60 minutes, after which thereverse transcriptase was inactivated by treatment at 95° C. for 10minutes. The obtained cDNA was supplied to a PCR using a Gene Amp PCRsystem 9700. The obtained cDNA was quantitated using an SYBR Green PCRCore Reagents kit (Applied Biosystems), and the human CYP3A4 and GAPDHmRNA was quantitated using an ABI7700 (Applied Biosystems). The primersequences and conditions used in the PCR are shown in Tables 3 and 4.The abbreviations used in the test example are explained below.

FBS: Fetal Bovine Serum

PSG: Penicillin (100 U/ml), Streptomycin (100 μg/ml), Glutamine (2 mM)

EGF: Epidermal Growth Factor

GAPDH: Glyceraldehyde-3-Phosphate Dehydrogenase TABLE 3 Primer Sequences(SEQ ID NOS: 1-4) Isozyme GenBank# Primer Name Sequence CYP3A4 NM017460F HCYP3A4_F3 TAGCTGAGGATGAAGAATGG R HCYP3A4_R3 GTGGATTGTTGAGAGAGTCGGAPDH M_33197 F hGAPDH_F GAAGGTGAAGGTCGGAGTC R hGAPDH_RGAAGATGGTGATGGGATTTC

TABLE 4 PCR Conditions Temperature Time 95 10 min 94 15 s denature 56 15s annealing 72 30 s extension40 cycles(2) Calculation of CYP3A4 Inducibility:

The obtained data were processed in the following manner. The value ofthe amount of CYP3A4 mRNA obtained by PCR divided by the amount of GAPDHmRNA was calculated, and the ratio (“fold”) of the value obtained byaddition of the test compound with respect to the value of the negativecontrol (0.1% DMSO), and the ratio of the positive control value (10 μMrifampicin) with respect to the negative control value, were bothcalculated. Next, for comparison of each test run, the differencesbetween the value of the CYP3A4 mRNA amount divided by the GAPDH mRNAamount with addition of the test compound at various concentrations andwith addition of the negative control were calculated as percentages,with 100% being defined as the difference between the values of theCYP3A4 mRNA amount divided by the GAPDH mRNA amount for the positivecontrol and negative control, to determine the inducibility of each testcompound.

<Test Results>

In Test Example 4, the compounds of the invention (Examples 1, 3, 59)were evaluated the induction of drug metabolizing enzyme withcryopreserved human hepatocytes in order to estimate the CYP inductionin liver, to predict drug interactions as side effects of concern foradministration as treatment for humans. The test results for testcompound concentrations of 1 μM indicated weak inducibility of nogreater than 40%, where the “fold” value for the positive control wasdefined as 100%. Some of the test results obtained using the testcompounds are shown in Table 5. TABLE 5 % of Positive Control Testconcentration Examples 0.03 μM 0.1 μM 0.3 μM 1 μM 3 μM 10 μM Example 592 3 11 25 49 59 Example 1 6 7 12 20 36 65 Example 3 3 3  7 25 23 34Rifampicine — — — — — 100 (positive control)

Various other assays were also employed in addition to Test Example 4above in order to evaluate the drug metabolizing enzyme inducibilities,and the compounds of the present invention were confirmed to have lowinducibilities for those various drug metabolizing enzymes as well.

INDUSTRIAL APPLICABILITY

The present invention can provide a novel pharmaceutical compositioncomprising a novel pyrazolo[1,5-a]pyridine compound having CRF receptorantagonism, a salt thereof or a hydrate of the foregoing. A compound ofthe present invention, a salt thereof or a hydrate of the foregoing hasexcellent antagonism against CRF receptor, especially against CRF1receptor, and their toxicity is low and their safety is high, therefore,their usefulness as medicine is high. A compound of the presentinvention or the like and a pharmaceutical composition comprising themare useful for the therapy or prevention for a disease associated withCRF and/or CRF receptor, especially for depression, depressive symptoms(major depression, single-episode depression, recurrent depression,depression-induced child abuse, postpartum depression, etc.), mania,anxiety, generalized anxiety disorder, panic disorder, phobias,obsessive-compulsive disorder, posttraumatic stress disorder, Tourette'ssyndrome, autism, affective disorder, dysthymia, bipolar disorder,cyclothymic personality, schizophrenia, peptic ulcer, irritable bowelsyndrome, ulcerative colitis, Crohn's disease, diarrhea, constipation,postoperative ileus, stress-associated gastrointestinal disorders,nervous vomiting or the like.

1. 4-(Hydroxymethyl)-2,6-dimethoxyphenylboric acid represented by thefollowing formula: